Benzimidazole derivatives as MCH receptor antagonists

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) N-(5-Iodopyridin-2-yl)-4-methylbenzenesulfonamide

A mixture of 5-iodopyridin-2-amine (25.5 g), 4-methylbenzene-1-sulfonyl chloride (23.2 g) and pyridine (250 ml) was heated at 100° C. overnight. The mixture was poured into water (1.2 L) with stirring, and the resulting precipitate was collected by filtration. The solid was washed with water and Et 2 O successively, and dried in vacuo to give the title compound (37.4 g) as a white solid.

MS (ESI+): [M+H]+ 374.9.

B) N-(1-(1-Cyclopropyl-1-oxopropan-2-yl)-5-iodopyridin-2(1H)-ylidene)-4-methylbenzenesulfonamide

To a solution of N-(5-iodopyridin-2-yl)-4-methylbenzenesulfonamide (33.1 g) in DMF (400 ml) was added NaH (40% oil dispersion, 3.89 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Then 2-bromo-1-cyclopropylpropan-1-one (23.5 g) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , and concentrated. The resulting solid was suspended in IPE, stirred for 1 h, and collected by filtration. The crude product was dissolved in EtOAc (1100 ml) at 70° C., and hexane (400 ml) was added while the temperature was maintained at 60° C. Seed crystal was added, and the mixture was stirred at the same temperature for 1 h. Additional hexane (400 ml) was added at 60° C., and the mixture was allowed to cool to room temperature overnight. The precipitate was collected by filtration, washed with hexane/EtOAc (1/1) 3 times, and dried to give the title compound (30.5 g) as a white solid.

MS (ESI+): [M+H]+ 470.9.

C) 2-Cyclopropyl-6-iodo-3-methylimidazo[1,2-a]pyridine

To a solution of N-(1-(1-cyclopropyl-1-oxopropan-2-yl)-5-iodopyridin-2(1H)-ylidene)-4-methylbenzene sulfonamide (30.5 g) in THF (300 ml) was added trifluoroacetic anhydride (18.3 ml) dropwise. After 3 h, the resulting precipitate was collected by filtration, and washed with ether to give p-toluenesulfonic acid salt of the title compound as a white solid. The solid obtained was dissolved in a mixture of 1 M NaOH, EtOAc and THF. Then the organic layer was washed with brine, dried over MgSO 4 and concentrated. The resulting solid was triturated with IPE, and collected to give the title compound (17.7 g) as a pale yellow solid.

MS (ESI+): [M+H]+ 299.0.

D) 1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

To a stirred degassed mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (200 mg), 2-cyclopropyl-6-iodo-3-methylimidazo[1,2-a]pyridine (285 mg) and potassium carbonate (378 mg) in DMF (6 ml) were added copper iodide (34.7 mg) and trans-N,N′-dimethylcyclohexane-1,2-diamine (26 mg). The reaction vessel was sealed and heated at 130° C. for 16 h. DMF was removed in vacuo and then the residue was partitioned between EtOAc (100 ml) and water (20 ml). The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. Two batches were combined and purified by preparative HPLC to give the title compound (80 mg) as an off-white solid.

MS (ESI+): [M+H]+ 389.8.

1 H NMR (400 MHz, CD 3 OD): δ 0.95-0.99 (4H, m), 2.06 (1H, m), 2.51 (3H, s), 5.14 (2H, s), 6.11 (1H, d, J=2.6 Hz), 6.28 (1H, dd, J=2.6, 7.6 Hz), 7.14 (2H, t, J=8.7 Hz), 7.21 (1H, dd, J=1.9, 9.4 Hz), 7.46-7.51 (3H, m), 7.60 (1H, d, J=7.6 Hz), 8.33 (1H, d, J=1.3 Hz).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) 5-Bromo-N-methyl-2-nitroaniline

To a solution of 4-bromo-2-fluoro-1-nitrobenzene (25 g) in EtOH (100 ml) was added methylamine (40% in MeOH, 34.8 ml) at room temperature. The mixture was stirred at room temperature for 1 h. After being stirred, the reaction mixture was cooled to 0° C., and the precipitate was collected by filtration and washed with EtOH (0° C.) and IPE. The solid was dried to give the title compound (24.8 g) as a yellow solid.

1 H NMR (300 MHz, DMSO-d 6 ): δ 2.95 (3H, d, J=4.9 Hz), 6.83 (1H, dd, J=1.9, 9.1 Hz), 7.17 (1H, d, J=1.9 Hz), 7.98 (1H, d, J=9.1 Hz), 8.23 (1H, brs).

B) 6-Bromo-2-cyclopropyl-1-methyl-1H-benzimidazole

A mixture of 5-bromo-N-methyl-2-nitroaniline (4.2 g), zinc (5.9 g), NH 4 Cl (9.7 g), MeOH (50 ml) and water (25 ml) was stirred at room temperature for 3 h. After removing MeOH, the mixture was neutralized with saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. To a solution of the residue in POCl 3 (1.68 ml) was added cyclopropanecarboxylic acid (2.86 ml) at room temperature. The mixture was stirred at 120° C. for 3 h. After cooling to 0° C., ice water and saturated NaHCO 3 solution were carefully added, and the mixture was extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated to give a brown solid. This solid was dissolved in 1 M HCl and washed with EtOAc. The aqueous layer was basified with 4 M NaOH, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO 4 , and concentrated to give the title compound (3.3 g) as a brown solid.

1 H NMR (300 MHz, DMSO-d 6 ): δ 0.95-1.14 (4H, m), 2.23 (1H, tt, J=5.1, 7.9 Hz), 3.83 (3H, s), 7.24 (1H, dd, J=2.1, 8.5 Hz), 7.41 (1H, d, J=8.7 Hz), 7.75 (1H, d, J=1.9 Hz).

C) 1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (2.44 g), 6-bromo-2-cyclopropyl-1-methyl-1H-benzimidazole (2.8 g), potassium carbonate (4.62 g), N,N′-dimethylethylenediamine (1.20 ml), copper iodide (2.12 g) and DMSO (56 ml) was stirred at 150° C. under Ar atmosphere for 2 h. After cooling to 0° C., 28% NH 3 solution (56.0 ml) was added. The mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h. The precipitate was collected by filtration and washed with water and IPE. The collected material was dissolved in THF (500 ml), passed through a short NH silica gel column (EtOAc 100%) and concentrated in vacuo. The resulting solid was collected, washed with IPE (50 ml) and then EtOAc (50 ml), and dissolved in MeOH. To the solution was added activated carbon (ca. 200 mg), and the mixture was stirred at room temperature for 10 min. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc), and recrystallized from EtOH/water to give the title compound (1.60 g) as an off-white solid.

MS (ESI+): [M+H]+ 390.2.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.99-1.15 (4H, m), 2.20-2.33 (1H, m), 3.85 (3H, s), 5.13 (2H, s), 5.98 (1H, d, J=2.3 Hz), 6.09 (1H, dd, J=2.4, 7.5 Hz), 7.04 (1H, d, J=8.6 Hz), 7.26 (2H, t, J=8.8 Hz), 7.43-7.67 (5H, m).

4-((4-Chlorobenzyl)oxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (1.0 g), 2-cyclopropyl-6-iodo-3-methylimidazo[1,2-a]pyridine (1.27 g), N,N′-dimethylethylenediamine (0.48 ml), copper iodide (0.81 g), potassium carbonate (1.76 g) and DMSO (15 ml) was heated at 150° C. for 3 h. Another batch of the same reaction was conducted. Then these reaction mixtures were combined, and poured into 14% NH 3 solution. The mixture was extracted with 1:1 mixture of EtOAc and THF. The extract was washed with brine, dried over MgSO 4 , concentrated, and purified by silica gel column chromatography (EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc) to give a white solid (350 mg).

Then a mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (1.0 g), 2-cyclopropyl-6-iodo-3-methylimidazo[1,2-a]pyridine (1.27 g), N,N′-dimethylethylenediamine (0.48 ml), copper iodide (0.81 g), potassium carbonate (1.76 g) and DMSO (13 ml) was heated at 110° C. under microwave irradiation for 1 h. Other two batches using 200 mg and 1 g of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one were conducted. Then these reaction mixtures were combined, and poured into 14% NH 3 solution. The mixture was extracted with 1:1 mixture of EtOAc and THF. The extract was washed with brine, dried over MgSO 4 , concentrated, and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc) to give the title compound as a white solid (950 mg).

These two lots were combined, and recrystallized from EtOH/water to give the title compound as a white solid (1.25 g).

MS (ESI+): [M+H]+ 406.1.

1 H NMR (300 MHz, DMSO-d 6 ): δ 0.84-0.96 (4H, m), 2.01-2.13 (1H, m), 2.47 (3H, s), 5.16 (2H, s), 6.00 (1H, d, J=2.6 Hz), 6.14 (1H, dd, J=2.6, 7.6 Hz), 7.11 (1H, dd, J=1.9, 9.4 Hz), 7.43 (1H, d, J=9.4 Hz), 7.50 (4H, s), 7.66 (1H, d, J=7.6 Hz), 8.36 (1H, d, J=1.1 Hz).

1-(2-Cyclopropyl-1,4-dimethyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) 5-Bromo-3-methylbenzene-1,2-diamine

To a stirred solution of compound 4-bromo-2-methyl-6-nitroaniline (5.0 g) in EtOH (85 ml) and water (43 ml) were added iron powder (6.0 g) and CaCl 2 (4.8 g) at room temperature and the resulting reaction mixture was then heated at reflux for 4 h. The mixture was then cooled to room temperature, filtered through Celite, and washed with EtOH. The filtrate was concentrated and the resulting residue was diluted with DCM. The DCM layer was successively washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo to give the title compound (4.0 g) as a dark brown solid.

MS (ESI+): [M+H]+ 201.2.

B) Ethyl(2-amino-5-bromo-3-methylphenyl)carbamate

To a stirred solution of 5-bromo-3-methylbenzene-1,2-diamine (4 g) in DMF (80 ml) was added NaH (40% oil dispersion, 800 mg) at 0° C., and the reaction mixture was stirred for another 30 min at the same temperature. A solution of ethyl chloroformate (1.9 g) in DMF (10 ml) was added dropwise thereto at 0° C. and then the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into saturated NH 4 Cl solution, and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (2.5 g) as a yellow solid.

MS (ESI+): [M+H]+ 273.1.

C) 5-Bromo-N 1 ,3-dimethylbenzene-1,2-diamine

To a stirred suspension of lithium aluminum hydride (400 mg) in THF (25 ml) was added a solution of ethyl(2-amino-5-bromo-3-methylphenyl)carbamate (1 g) in THF (10 ml) at 0° C. The mixture was then warmed to room temperature, followed by heating at reflux for 1 h. The reaction mixture was cooled to 0° C., diluted with THF (45 ml) and a saturated Na 2 SO 4 solution was added dropwise thereto. The mixture was further stirred for 30 min and solids were filtered over Celite. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (550 mg) as a brownish liquid.

MS (ESI+): [M+H]+ 215.2.

D) 6-Bromo-2-cyclopropyl-1,4-dimethyl-1H-benzimidazole

To a stirred mixture of cyclopropanecarboxylic acid (356 μl) and 5-bromo-N′,3-dimethylbenzene-1,2-diamine (600 mg) was added POCl 3 (10 ml), and the mixture was heated at 120° C. After 3 h, the mixture was poured into saturated aqueous NaHCO 3 solution, and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (450 mg) as brown solid.

MS (ESI+): [M+H]+ 265.0.

E) 1-(2-Cyclopropyl-1,4-dimethyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

To a stirred degassed mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (66 mg), 6-bromo-2-cyclopropyl-1,4-dimethyl-1H-benzimidazole (100 mg), potassium carbonate (156 mg) and dioxane (2 ml) were added copper iodide (14 mg) and trans-N,N′-dimethylcyclohexane-1,2-diamine (10 mg). The reaction vessel was sealed and heated at 110° C. for 16 h. The mixture was then cooled, filtered through Celite, and washed with dioxane. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (MeOH/DCM) followed by preparative HPLC to give the title compound (60 mg) as an off-white solid.

MS (ESI+): [M+H]+ 404.0.

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-(trifluoromethyl)benzyl)oxy)pyridin-2(1H)-one

A) 4-((4-(Trifluoromethyl)benzyl)oxy)pyridine 1-oxide

To an ice-cold solution of NaH (40% oil dispersion, 231 mg) in THF (10 ml) was added (4-(trifluoromethyl)phenyl)methanol (815 mg) at 0° C. The reaction mixture was stirred at the same temperature for 10 min followed by the addition of 4-chloropyridine 1-oxide (500 mg) at 0° C. The resulting reaction mixture was stirred for 1 h at 0° C. and then warmed to room temperature. After 2 h, the reaction mixture was poured into ice-water and extracted with DCM twice. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the title compound (300 mg) as a yellow solid.

MS (ESI+): [M+H]+ 270.2.

B) 4-((4-(Trifluoromethyl)benzyl)oxy)pyridin-2(1H)-one

A solution of 4-((4-(trifluoromethyl)benzyl)oxy)pyridine 1-oxide (350 mg) in acetic anhydride (6 ml) was heated under reflux for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with MeOH (10 ml) and 2 M NaOH (10 ml), and heated at reflux for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted with DCM. The DCM layer was concentrated in vacuo and purified by silica gel column chromatography (MeOH/DCM) to give the title compound (110 mg) as an off-white solid.

MS (ESI+): [M+H]+ 270.0.

C) 1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-(trifluoromethyl)benzyl)oxy)pyridin-2(1H)-one

To a stirred degassed mixture of 4-((4-(trifluoromethyl)benzyl)oxy)pyridin-2(1H)-one (110 mg), 2-cyclopropyl-6-iodo-3-methylimidazo[1,2-a]pyridine (121 mg), potassium carbonate (168 mg) and dioxane (10 ml) were added copper iodide (15 mg) and trans-N,N′-dimethylcyclohexane-1,2-diamine (11 mg). The reaction vessel was sealed and heated at 110° C. for 16 h. The mixture was filtered through a Celite pad, and the filtrate was concentrated in vacuo. The residue was diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (40 mg) as an off-white solid.

MS (ESI+): [M+H]+ 440.2.

1 H NMR (400 MHz, CD 3 OD): δ 0.95-1.01 (4H, m), 2.06 (1H, m), 2.51 (3H, s), 5.28 (2H, s), 6.10 (1H, d, J=2.4 Hz), 6.33 (1H, dd, J=2.4, 7.6 Hz), 7.21 (1H, dd, J=2.0, 9.2 Hz), 7.47 (1H, d, J=9.6 Hz), 7.62-7.67 (3H, m), 7.72 (2H, d, J=8.4 Hz), 8.33 (1H, s).

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-(trifluoromethoxy)benzyl)oxy)pyridin-2(1H)-one

A) 4-((4-(Trifluoromethoxy)benzyl)oxy)pyridine 1-oxide

The title compound was obtained in an analogous manner to step A in example 5 using (4-(trifluoromethoxy)phenyl)methanol.

MS (ESI+): [M+H]+ 286.0.

B) 4-((4-(Trifluoromethoxy)benzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step B in example 5 using 4-((4-(trifluoromethoxy)benzyl)oxy)pyridine 1-oxide.

MS (ESI+): [M+H]+ 286.0.

C) 1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-(trifluoromethoxy)benzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-(trifluoromethoxy)benzyl)oxy)pyridin-2(1H)-one and 2-cyclopropyl-6-iodo-3-methylimidazo[1,2-a]pyridine.

MS (ESI+): [M+H]+ 456.4.

6-((4-Chlorobenzyl)oxy)-3-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyrimidin-4(3H)-one

A) (2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)boronic acid

To a solution of 2-cyclopropyl-6-iodo-3-methylimidazo[1,2-a]pyridine (742 mg) in THF (25 ml) was added n-butyllithium (1.6 M in hexane, 6.2 ml) at −78° C. The mixture was stirred at −78° C. under N 2 atmosphere for 30 min. After being stirred, boric acid triisopropyl ester (0.86 ml) was added to the reaction mixture at −78° C. The mixture was stirred at −78° C. under N 2 atmosphere for 30 min and then at room temperature for 3 h. The mixture was poured into 1 M NaOH at 0° C. and washed with EtOAc. The aqueous layer was neutralized with 1 M HCl (to pH 7.0) and extracted with EtOAc/IPA. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The resulting solid was washed with EtOAc/MeOH to give the title compound (176 mg) as a yellow solid.

MS (ESI+) [M+H]+ 217.2.

B) 6-((4-Chlorobenzyl)oxy)pyrimidin-4(3H)-one

To a stirred solution of pyrimidine-4,6-diol (2.5 g) in THF (25 ml) was added silver carbonate (15.3 g) at room temperature followed by dropwise addition of 4-chlorobenzyl bromide (4.58 g), and the resultant mixture was heated at reflux for 2 h. The reaction mixture was then cooled to room temperature, filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (500 mg) as a white solid.

MS (ESI+): [M+H]+ 237.2.

C) 6-((4-Chlorobenzyl)oxy)-3-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyrimidin-4(3H)-one

To a mixture of 6-((4-chlorobenzyl)oxy)pyrimidin-4(3H)-one (150 mg), (2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)boronic acid (275 mg), DCM (15 ml) and MeOH (15 ml) were added copper acetate (346 mg) and pyridine (0.5 ml), and the resulting reaction mixture was stirred at room temperature for 16 h. The solids were then filtered through Celite, and the filtrate was poured into 1 M HCl. The mixture was extracted with DCM, and the combined DCM layer was washed successively with saturated NaHCO 3 solution, brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (15 mg) as an off-white solid.

MS (ESI+): [M+H]+ 407.0.

1-(2-tert-Butyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) 6-Bromo-2-tert-butyl-1-methyl-1H-benzimidazole

To a stirred solution of 2,2-dimethylpropionic acid (304 mg) and 4-bromo-N 2 -methylbenzene-1,2-diamine (400 mg) was added POCl 3 (5 ml), and the mixture was heated at reflux for 4 h. The mixture was then cooled to room temperature, and poured into ice-cold saturated NaHCO 3 solution. The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (200 mg) as a light orange solid.

MS (ESI+): [M+H]+ 266.6.

B) 1-(2-tert-Butyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 6-bromo-2-tert-butyl-1-methyl-1H-benzimidazole.

MS (ESI+): [M+H]+ 405.9.

4-(Benzyloxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 4-(benzyloxy)pyridin-2(1H)-one (1.60 g), 6-bromo-2-cyclopropyl-1-methyl-1H-benzimidazole (2 g), potassium carbonate (3.30 g), N,N′-dimethylethylenediamine (0.855 ml), copper iodide (1.52 g) and DMSO (40 ml) was stirred at 150° C. under Ar atmosphere for 1 h. The mixture was poured into 28% NH 3 solution. The precipitate was collected by filtration and washed with water and EtOAc. The solid was dissolved in THF, put on through silica gel pad and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/MeOH). The resulting solid was dissolved in MeOH, and stirred with activated charcoal at room temperature for 10 min. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound (1.60 g) as an off-white solid.

MS (ESI+): [M+H]+ 372.2.

1 H NMR (300 MHz, DMSO-d 6 ) δ 0.95-1.19 (4H, m), 2.18-2.34 (1H, m), 3.85 (3H, s), 5.15 (2H, s), 5.98 (1H, d, J=3.0 Hz), 6.10 (1H, dd, J=2.6, 7.6 Hz), 6.96-7.11 (1H, m), 7.29-7.66 (8H, m).

4-((4-Chlorobenzyl)oxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a stirred degassed mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (502 mg), 6-bromo-2-cyclopropyl-1-methyl-1H-benzimidazole (470 mg), potassium carbonate (552 mg) and dry dioxane (15 ml) were added copper iodide (76 mg) and trans-N,N′-dimethylcyclohexane-1,2-diamine (56 mg). The reaction vessel was sealed and heated at 110° C. for 16 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The crude residue was diluted with DCM, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (150 mg) as a white solid.

MS (ESI+): [M+H]+ 406.0.

1 H NMR (400 MHz, CD 3 OD): δ 1.14-1.20 (4H, m), 2.24 (1H, m), 3.90 (3H, s), 5.16 (2H, s), 6.09 (1H, d, J=2.6 Hz), 6.27 (1H, dd, J=2.7, 7.6 Hz), 7.15 (1H, dd, J=2.0, 8.5 Hz), 7.41-7.50 (5H, m), 7.69 (2H, t, J=8.3 Hz).

4-(Benzyloxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

A mixture of 2-cyclopropyl-6-iodo-3-methylimidazo[1,2-a]pyridine (1482 mg), 4-(benzyloxy)pyridin-2(1H)-one (1000 mg), copper iodide (946 mg), N,N′-dimethylethylenediamine (0.534 ml), potassium carbonate (2061 mg) and DMSO (13 ml) was heated 110° C. for 1 h under microwave irradiation. The residue was quenched with 28% NH 3 solution, and extracted with EtOAc/THF. The organic layer was separated, washed with water and brine, dried over MgSO 4 , passed through silica gel pad (EtOAc only) and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/MeOH) and recrystallized from EtOH (80 ml) to give the title compound (1027 mg) as an off-white solid.

MS (ESI+): [M+H]+ 372.2.

1 H NMR (300 MHz, DMSO-d 5 ): δ 0.83-0.96 (4H, m), 2.02-2.12 (1H, m), 2.47 (3H, s), 5.16 (2H, s), 6.01 (1H, d, J=2.6 Hz), 6.09-6.18 (1H, m), 7.11 (1H, dd, J=1.9, 9.4 Hz), 7.32-7.53 (6H, m), 7.66 (1H, d, J=7.5 Hz), 8.37 (1H, d, J=1.1 Hz).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol and 1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one.

MS (ESI+): [M+H]+ 444.1.

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(tetrahydrofuran-3-yl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) 4-((4-Fluorobenzyl)oxy)-1-(3-(methylamino)-4-nitrophenyl)pyridin-2(1H)-one

A mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (2.06 g), 5-bromo-N-methyl-2-nitroaniline (2.17 g), N,N′-dimethylethylenediamine (1.00 ml), copper iodide (1.79 g), potassium carbonate (3.90 g) and DMSO (30 ml) was stirred at 150° C. for 2 h. The mixture was added to 28% NH 3 solution. The precipitate was collected and washed with water to give the title compound (2.63 g) as a yellow solid.

MS (ESI+): [M+H]+ 370.1.

B) 1-(4-Amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

To a suspension of 4-((4-fluorobenzyl)oxy)-1-(3-(methylamino)-4-nitrophenyl)pyridin-2(1H)-one (500 mg) in AcOH (30 ml) was added zinc (885 mg), and the mixture was stirred at room temperature for 1 h. The insoluble material was removed by filtration and washed with MeOH. The filtrate was concentrated, and partitioned between EtOAc, THF and saturated NaHCO 3 solution. The organic layer was then washed with brine, dried over MgSO 4 , and concentrated. The resulting solid was collected, and washed with IPE to give the title compound (366 mg) as a brown solid.

MS (ESI+): [M+H]+ 340.3.

C) 4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(tetrahydrofuran-3-yl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (56.1 mg), tetrahydro-3-furoic acid (0.016 ml), HATU (66.0 mg) and N,N-diisopropylethylamine (0.087 ml) in DMF (1.50 ml) was stirred at room temperature for 1 h. The mixture was poured into saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was dissolved in AcOH (1.50 ml), and the mixture was stirred at 80° C. for 1 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/EtOAc). The solid was washed with EtOAc/hexane to give the title compound (34.3 mg) as an off-white solid.

MS (ESI+): [M+H]+ 420.1.

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) 6-Bromo-1-methyl-2-(trichloromethyl)-1H-benzimidazole

A mixture of 5-bromo-N-methyl-2-nitroaniline (0.65 g), iron (0.63 g), CaCl 2 (0.62 g), EtOH (14 ml) and water (14 ml) was heated at 70° C. for 3 h. The inorganic material was removed by filtration, and the filtrate was concentrated. The residue was basified with saturated NaHCO 3 , and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , and concentrated to give the title compound (0.51 g) as a brown oil.

To the oil in AcOH (3 ml), methyl 2,2,2-trichloroacetimidate (0.42 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 2 h. After addition of water, the precipitate was collected by filtration and washed with water to give the title compound (0.78 g) as a gray solid.

1 H NMR (300 MHz, CDCl 3 ): δ 4.09 (3H, s), 7.46 (1H, dd, J=1.7, 8.5 Hz), 7.58 (1H, d, J=1.5 Hz), 7.74 (1H, d, J=8.7 Hz).

B) Methyl 6-bromo-1-methyl-1H-benzimidazole-2-carboxylate

A mixture of 6-bromo-1-methyl-2-(trichloromethyl)-1H-benzimidazole (0.781 g), sodium carbonate (0.298 g), MeOH (20 ml), and water (2 ml) was refluxed overnight. After evaporation of the solvent and addition of water, the mixture was extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The solid was washed with Et 2 O to give the title compound (0.315 g) as a pale brown solid.

1 H NMR (300 MHz, CDCl 3 ): δ 4.05 (3H, s), 4.14 (3H, s), 7.46 (1H, dd, J=1.9, 8.7 Hz), 7.63 (1H, d, J=1.5 Hz), 7.74 (1H, d, J=8.7 Hz).

C) 4-((4-Fluorobenzyl)oxy)-1-(1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and methyl 6-bromo-1-methyl-1H-benzimidazole-2-carboxylate.

MS (ESI+): [M+H]+ 350.2.

1-(2-(Cyclopropylmethyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) 6-Bromo-2-(cyclopropylmethyl)-1-methyl-1H-benzimidazole

Zinc (212 mg) was added to a mixture of 5-bromo-N-methyl-2-nitroaniline (150 mg), NH 4 Cl (347 mg), MeOH (2 ml) and water (1 ml) at room temperature. The mixture was stirred at room temperature for 1 h. After filtration and addition of saturated NaHCO 3 solution, the mixture was concentrated and extracted with AcOEt. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. To the resulting residue, DMF (2.0 ml), cyclopropylacetic acid (0.060 ml), N,N-diisopropylethylamine (0.339 ml) and HATU (259 mg) were added, and the mixture was stirred at room temperature for 1 h. The mixture was quenched with brine and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO 4 , passed through NH silica pad and concentrated in vacuo. The resulting residue was dissolved in AcOH (2.0 ml), and stirred at 80° C. for 1 h. After evaporation of the solvent, the residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (165 mg) as a purple gum.

MS (ESI+): [M+H]+ 265.1.

B) 1-(2-(Cyclopropylmethyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (91 mg), 6-bromo-2-(cyclopropylmethyl)-1-methyl-1H-benzimidazole (165 mg), N,N′-dimethylethylenediamine (0.045 ml)-, copper iodide (79 mg), potassium carbonate (229 mg) and DMSO (3 ml) was heated at 150° C. for 2 h under microwave irradiation. After cooling, the reaction mixture was purified by NH silica gel column chromatography (hexane/EtOAc to MeOH/EtOAc). The resulting solid was washed with EtOAc and dried to give the title compound (62 mg) as a pale yellow solid.

MS (ESI+): [M+H]+ 404.2.

1 H NMR (300 MHz, CDCl 3 ): δ 0.27-0.37 (2H, m), 0.57-0.68 (2H, m), 1.12-1.25 (1H, m), 2.87 (2H, d, J=6.4 Hz), 3.75 (3H, 5), 5.02 (2H, s), 5.96-6.13 (2H, m), 7.04-7.16 (3H, m), 7.31 (1H, d, J=7.2 Hz), 7.35-7.45 (3H, m), 7.79 (1H, d, J=8.3 Hz).

3-(6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)-2,2-dimethylpropanenitrile

A) 3-(6-Bromo-1-methyl-1H-benzimidazol-2-yl)-2,2-dimethylpropanenitrile

Thionyl chloride (0.454 ml) was added to a solution of (6-bromo-1-methyl-1H-benzimidazol-2-yl)methanol (300 mg) in THF (6 ml) at room temperature. The mixture was stirred at room temperature for 1 h and poured into water. After addition of NaHCO 3 solution, the mixture was extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo to give the corresponding chloride derivative. Lithium diisopropylamide in THF/ethylbenzene/heptane (2.0 M, 1.24 ml) was added to a solution of isobutyronitrile (0.226 ml) in THF (6 ml) at −78° C. The mixture was stirred at −78° C. under Ar atmosphere for 1 h. To this mixture, a solution of the chloride derivative in THF (2 ml) was added dropwise. The mixture was stirred at −78° C. under Ar atmosphere for 1 h and warmed up to room temperature. The mixture was stirred at room temperature overnight. The mixture was quenched with brine and extracted with EtOAc three times. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (25.5 mg) as a light brown oil.

MS (ESI+): [M+H]+ 292.1.

B) 3-(6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)-2,2-dimethylpropanenitrile

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 3-(6-bromo-1-methyl-1H-benzimidazol-2-yl)-2,2-dimethylpropanenitrile.

MS (ESI+): [M+H]+ 431.2.

1-(2-(2,2-Dimethylpropyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) N-(5-Bromo-2-nitrophenyl)-N,3,3-trimethylbutanamide

To a mixture of 5-bromo-N-methyl-2-nitroaniline (300 mg), 3,3-dimethylbutanoyl chloride (0.450 ml) and DMF (5 ml) was added NaH (40% oil dispersion, 57.1 mg), and the mixture was heated at 70° C. overnight. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (214 mg) as a solid.

1 H NMR (300 MHz, DMSO-d 6 ): δ 0.86-1.06 (9H, m), 1.67-2.39 (2H, m), 3.02-3.45 (3H, m), 7.68-8.13 (3H, m).

B) 6-Bromo-2-(2,2-dimethylpropyl)-1-methyl-1H-benzimidazole

To a solution of N-(5-bromo-2-nitrophenyl)-N,3,3-trimethylbutanamide (300 mg) in AcOH (5 ml) was added zinc (596 mg) at room temperature. Then the mixture was heated at 90° C. for 2 h. The inorganic material was removed by filtration, and the filtrate was concentrated. The residue was poured into a mixture of EtOAc and saturated NaHCO 3 solution. The organic layer was washed with brine, dried over MgSO 4 , concentrated, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (200 mg) as a white solid.

MS (ESI+): [M+H]+ 281.0.

C) 1-(2-(2,2-Dimethylpropyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (78 mg), 6-bromo-2-(2,2-dimethylpropyl)-1-methyl-1H-benzimidazole (100 mg), N,N′-dimethylethylenediamine (31 mg), copper iodide (68 mg), potassium carbonate (147 mg) and DMSO (2 ml) was heated under Ar atmosphere at 150° C. for 2 h. The mixture was partitioned between 14% aqueous NH 3 and EtOAc. The organic layer was washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (50 mg) as a white solid.

MS (ESI+): [M+H]+ 420.2.

4-((4-Chlorobenzyl)oxy)-1-(2-(2,2-dimethylpropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 17 using 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one and 6-bromo-2-(2,2-dimethylpropyl)-1-methyl-1H-benzimidazole.

MS (ESI+): [M+H]+ 436.1.

1-(2-Cyclopropyl-1-propyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) 5-Bromo-2-nitro-N-propylaniline

The title compound was obtained in an analogous manner to step A in example 2 using n-propylamine.

1 H NMR (300 MHz, CDCl 3 ): δ 1.06 (3H, t, J=7.5 Hz), 1.77 (2H, m), 3.25 (2H, td, J=5.1, 7.1 Hz), 6.74 (1H, dd, J=1.9, 9.0 Hz), 7.01 (1H, d, J=1.9 Hz), 7.92-8.11 (2H, m).

B) 6-Bromo-2-cyclopropyl-1-propyl-1H-benzimidazole

The title compound was obtained in an analogous manner to step B in example 2 using 5-bromo-2-nitro-N-propylaniline.

MS (ESI+): [M+H]+ 281.0.

C) 1-(2-Cyclopropyl-1-propyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 2 using 6-bromo-2-cyclopropyl-1-propyl-1H-benzimidazole and 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one.

MS (ESI+): [M+H]+ 418.1.

1 H NMR (300 MHz, CDCl 3 ): δ 1.00 (3H, t, J=7.5 Hz), 1.08-1.18 (2H, m), 1.21-1.30 (2H, m), 1.90 (2H, q, J=7.4 Hz), 1.95-2.05 (1H, m), 4.20 (2H, t, J=7.3 Hz), 5.02 (2H, s), 5.99-6.13 (2H, m), 7.05-7.16 (3H, m), 7.28-7.37 (2H, m), 7.41 (2H, s), 7.70 (1H, d, J=8.3 Hz).

1-(2-Cyclopropyl-1-ethyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) 5-Bromo-N-ethyl-2-nitroaniline

The mixture of 4-bromo-2-fluoro-1-nitrobenzene (5 g) and ethylamine (2 M in THF, 17.05 ml) was stirred at room temperature for 2 h and at 50° C. for 2 h. After concentration of the mixture, the residue was quenched with saturated NaHCO 3 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The progress of the reaction was followed by NMR, but 4-bromo-2-fluoro-1-nitrobenzene was remained. The resulting residue was dissolved in EtOH (25 ml), and heated with potassium carbonate (6.28 g) and ethylamine (15.6 M in water, 1.47 ml) at 50° C. for 2 h. The resulting suspension was filtered. The precipitate was washed with EtOH and water and dried to give the title compound (4.45 g) as a pale yellow solid.

1 H NMR (300 MHz, CDCl 3 ): δ 1.06 (3H, t, J=7.5 Hz), 3.25 (2H, td, J=5.1, 7.1 Hz), 6.74 (1H, dd, J=1.9, 9.0 Hz), 7.01 (1H, d, J=1.9 Hz), 7.92-8.11 (2H, m).

B) 4-Bromo-N 2 -ethylbenzene-1,2-diamine

Zinc (8.0 g) was added to a solution of 5-bromo-N-ethyl-2-nitroaniline (3.0 g) in AcOH (60 ml) at room temperature. The mixture was stirred at room temperature for 30 min. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The mixture was neutralized with saturated NaHCO 3 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo to give the title compound (1.2 g) as a pale yellow solid.

MS (ESI+): [M+H]+ 217.1.

C) 6-Bromo-2-cyclopropyl-1-ethyl-1H-benzimidazole

HATU (4.89 g) was added to a solution of 4-bromo-N 2 -ethylbenzene-1,2-diamine (2.63 g), N,N-diisopropylethylamine (6.40 ml) and cyclopropanecarboxylic acid (0.979 ml) in DMF (40 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was dissolved into AcOH (40.0 ml), and the mixture was stirred at 80° C. for 1 h. After concentration of the mixture, the residue was neutralized with saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.2 g) as a pale yellow solid.

MS (ESI+): [M+H]+ 265.1.

D) 1-(2-Cyclopropyl-1-ethyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (100 mg), 6-bromo-2-cyclopropyl-1-ethyl-1H-benzimidazole (133 mg), copper iodide (87 mg), N,N′-dimethylethylenediamine (0.051 ml), potassium carbonate (158 mg) and DMSO (2.5 ml) was heated 120° C. for 1 h under microwave irradiation. The mixture was quenched with 28% NH 3 solution at room temperature and extracted with EtOAc and THF. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc). The solid was crystallized from IPA-hexane to give the title compound (113 mg) as an off-white solid.

MS (ESI+): [M+H]+ 404.2.

1 H NMR (300 MHz, CDCl 3 ): δ 1.09-1.18 (2H, m), 1.21-1.31 (2H, m), 1.47 (3H, t, J=7.3 Hz), 1.95-2.06 (1H, m), 4.30 (2H, q, J=7.2 Hz), 5.02 (2H, s), 6.00-6.10 (2H, m), 7.04-7.16 (3H, m), 7.30-7.38 (2H, m), 7.37-7.45 (2H, m), 7.70 (1H, d, J=8.7 Hz).

4-((4-Chlorobenzyl)oxy)-1-(2-cyclopropyl-1-ethyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (100 mg), 6-bromo-2-cyclopropyl-1-ethyl-1H-benzimidazole (124 mg), copper iodide (81 mg), N,N′-dimethylethylenediamine (0.048 ml), potassium carbonate (147 mg) and DMSO (2.5 ml) was heated 120° C. for 1 h under microwave irradiation. The mixture was quenched with 28% NH 3 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc). The solid was recrystallized from IPA/hexane to give the title compound (85 mg) as a light pink solid.

MS (ESI+): [M+H]+ 420.1.

1 H NMR (300 MHz, CDCl 3 ): δ 1.08-1.19 (2H, m), 1.20-1.31 (2H, m), 1.46 (3H, t, J=7.4 Hz), 1.93-2.05 (1H, m), 4.29 (2H, q, J=7.2 Hz), 5.02 (2H, s), 6.01-6.08 (2H, m), 7.10 (1H, dd, J=1.9, 8.7 Hz), 7.28-7.42 (6H, m), 7.70 (1H, d, J=8.3 Hz).

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((2,4-difluorobenzyl)oxy)pyridin-2(1H)-one

A) 1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one

To a stirred solution of 4-(benzyloxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (127 mg) in MeOH (8 ml) was added Pd/C (10%, 25 mg), and the mixture was stirred under H 2 atmosphere at room temperature for 4 h. The insoluble materials were then filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (56 mg) as an off-white solid.

MS (ESI+): [M+H]+ 282.2.

B) 1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((2,4-difluorobenzyl)oxy)pyridin-2(1H)-one

To a stirred suspension of NaH (40% oil dispersion, 19 mg) in THF (6 ml) was added a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2 (1H)-one (75 mg) in THF (1 ml) at 0° C., and then the mixture was stirred at room temperature for 30 min. 2,4-Difluorobenzyl bromide (67 mg) in THF (0.5 ml) was added, and the resulting mixture was stirred at room temperature for further 3 h followed by heating at reflux for 6 h. The reaction mixture was then cooled to room temperature and quenched with ice-water. The mixture was extracted with DCM, and the extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (38 mg) as an off-white solid.

MS (ESI+): [M+H]+ 408.2.

1 H NMR (400 MHz, CDCl 3 ): δ 0.96-1.04 (4H, m), 1.96 (1H, m), 2.47 (3H, s), 5.05 (2H, s), 6.04-6.06 (2H, m), 6.85-6.95 (2H, m), 7.03 (1H, dd, J=2.0, 9.2 Hz), 7.40-7.46 (2H, m), 7.53 (1H, d, J=9.2 Hz), 7.90 (1H, s).

1-(2-Cyclobutyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) 6-Bromo-2-cyclobutyl-1-methyl-1H-benzimidazole

The title compound was obtained in an analogous manner to step A in example 8 using 4-bromo-N 2 -methylbenzene-1,2-diamine and cyclobutanecarboxylic acid.

MS (ESI+): [M+H]+ 264.8.

B) 1-(2-Cyclobutyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 6-bromo-2-cyclobutyl-1-methyl-1H-benzimidazole.

MS (ESI+): [M+H]+ 404.0.

1-(2-(Difluoromethyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) 6-Bromo-2-(difluoromethyl)-1-methyl-1H-benzimidazole

The title compound was obtained in an analogous manner to step A in example 8 using 4-bromo-N 2 -methylbenzene-1,2-diamine and difluoroacetic acid.

MS (ESI+): [M+H]+ 264.8.

B) 1-(2-(Difluoromethyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 6-bromo-2-(difluoromethyl)-1-methyl-1H-benzimidazole.

MS (ESI+): [M+H]+ 399.8.

4-((4-Chlorobenzyl)oxy)-1-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

A) 6-Iodo-2,3-dimethylimidazo[1,2-a]pyridine

To a mixture of 3-bromobutan-2-one (1.0 g) and 2-amino-5-iodopyridine (800 mg) was added EtOH (25 ml), and the mixture was heated at 70° C. for 30 h. The reaction mixture was cooled, diluted with water, and extracted with DCM. The DCM layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (250 mg) as a yellow solid.

MS (ESI+): [M+H]+ 272.6.

B) 4-((4-Chlorobenzyl)oxy)-1-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a stirred degassed mixture of compound 6-iodo-2,3-dimethylimidazo[1,2-a]pyridine (190 mg), 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (150 mg), potassium carbonate (263 mg) and dioxane (10 ml) were added copper iodide (24 mg) and trans-N,N′-dimethylcyclohexane-1,2-diamine (18 mg). The reaction vessel was sealed and heated at 110° C. for 16 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM, and the DCM layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (120 mg) as an off-white solid.

MS (ESI+): [M+H]+ 379.8.

1 H NMR (400 MHz, DMSO-d 6 ): δ 2.33 (3H, s), 2.39 (3H, s), 5.17 (2H, s), 5.99 (1H, d, J=2.4 Hz), 6.14 (1H, dd, J=2.3, 7.6 Hz), 7.12-7.14 (1H, m), 7.45-7.49 (5H, m), 7.67 (1H, d, J=7.6 Hz), 8.38 (1H, s).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(pyridin-2-ylmethoxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using pyridine-2-ylmethanol and 1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one.

MS (ESI+): [M+H]+ 373.1.

4-((4-Chlorobenzyl)oxy)-1-(2-cyclopropyl-1-propyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (50 mg, 0.21 mmol), 6-bromo-2-cyclopropyl-1-propyl-1H-benzimidazole (65.2 mg, 0.23 mmol), copper iodide (40.4 mg, 0.21 mmol), N,N′-dimethylethylenediamine (0.024 ml, 0.21 mmol), potassium carbonate (73.3 mg, 0.53 mmol) and DMSO (1.5 ml) was heated at 120° C. for 1 h under microwave irradiation. The mixture was quenched with 28% NH 3 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc). The solid was recrystallized from EtOAc/hexane to give the title compound (10 mg) as an off-white solid.

MS (ESI+): [M+H]+ 434.2.

1 H NMR (300 MHz, CDCl 3 ): δ 1.00 (3H, t, J=7.5 Hz), 1.08-1.20 (2H, m), 1.23-1.33 (2H, m), 1.85-1.96 (2H, m), 1.96-2.04 (1H, m), 4.20 (2H, t, J=7.3 Hz), 5.02 (2H, s), 6.00-6.13 (2H, m), 7.01-7.16 (3H, m), 7.28-7.36 (2H, m), 7.37-7.45 (2H, m), 7.70 (1H, d, J=8.3 Hz).

1-(2-Cyclopropyl-3,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) 2-Cyclopropyl-6-iodo-3,8-dimethylimidazo[1,2-a]pyridine

A mixture of 5-iodo-3-methylpyridin-2-amine (100 mg), 2-bromo-1-cyclopropylpropan-1-one (113 mg) and DMF (1 ml) was stirred at 80° C. under a dry atmosphere (CaCl 2 tube) overnight. The mixture was quenched with saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (69.3 mg) as a pale yellow oil.

MS (ESI+): [M+H]+ 313.0.

B) 1-(2-Cyclopropyl-3,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 2-cyclopropyl-6-iodo-3,8-dimethylimidazo[1,2-a]pyridine.

MS (ESI+): [M+H]+ 404.2.

4-((4-Chlorobenzyl)oxy)-1-(2-(methoxymethyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) N-(5-Bromo-2-nitrophenyl)-2-methoxy-N-methylacetamide

To a solution of 5-bromo-N-methyl-2-nitroaniline (500 mg) in THF (10 ml) was added NaH (40% oil dispersion, 104 mg) at 0° C. The mixture was stirred at 0° C. under a dry atmosphere (CaCl 2 tube) for 30 min. After being stirred, methoxyacetyl chloride (0.237 ml) was added to the reaction mixture. The mixture was stirred at 60° C. under a dry atmosphere (CaCl 2 tube) for 3 h and then at room temperature overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc). The resulting solid was washed with Et 2 O to give the title compound (478 mg) as a pale yellow solid.

MS (ESI+): [M+H]+ 305.0.

B) 6-Bromo-2-(methoxymethyl)-1-methyl-1H-benzimidazole

To a solution of N-(5-bromo-2-nitrophenyl)-2-methoxy-N-methylacetamide (477 mg) in AcOH (8 ml) was added zinc (400 mg) at 0° C. The mixture was stirred at 80° C. under a dry atmosphere (CaCl 2 tube) for 3 h and then at room temperature overnight. The mixture was neutralized with saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (306 mg) as a pale yellow oil.

MS (ESI+): [M+H]+ 257.0.

C) 4-((4-Chlorobenzyl)oxy)-1-(2-(methoxymethyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one and 6-bromo-2-(methoxymethyl)-1-methyl-1H-benzimidazole.

MS (ESI+): [M+H]+ 410.1.

4-((4-Chlorobenzyl)oxy)-1-(2-isopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) 6-Bromo-2-isopropyl-1-methyl-1H-benzimidazole

To a solution of 5-bromo-N 1 -methylbenzene-1,2-diamine (122 mg) and isobutyric acid (0.056 ml) in DMF (2 ml) was added HATU (242 mg) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl 2 tube) for 1 h. After being stirred, N,N-diisopropylethylamine (0.311 ml) was added to the reaction mixture. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The resulting residue was stirred in AcOH (2.00 ml) at 90° C. for 1 h and at room temperature overnight. The mixture was quenched with saturated NaHCO 3 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (119 mg) as a pale yellow solid.

MS (ESI+): [M+H]+ 255.0.

B) 4-((4-Chlorobenzyl)oxy)-1-(2-isopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one and 6-bromo-2-isopropyl-1-methyl-1H-benzimidazole.

MS (ESI+): [M+H]+ 408.2.

1-(2-(Cyclopropylcarbonyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) 6-Bromo-N-methoxy-N,1-dimethyl-1H-benzimidazole-2-carboxamide

NaHCO 3 (717 mg) was added to a mixture of 6-bromo-1-methyl-2-(trichloromethyl)-1H-benzimidazole (400 mg), N,0-dimethylhydroxylamine hydrochloride (357 mg), NaHCO 3 (512 mg), CH 3 CN (6 ml) and water (2 ml) at room temperature. The mixture was stirred at 60° C. overnight. The mixture was quenched with brine and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (134 mg) as an orange gum.

MS (ESI+): [M+H]+ 298.0.

B) (6-Bromo-1-methyl-1H-benzimidazol-2-yl)(cyclopropyl)methanone

Cyclopropylmagnesium bromide (0.70 M in THF, 7.19 ml) was added dropwise to a solution of 6-bromo-N-methoxy-N,1-dimethyl-1H-benzimidazole-2-carboxamide (1.00 g) in THF (3 ml) at 0° C. The mixture was stirred at 0° C. under Ar atmosphere for 30 min. The mixture was quenched with saturated NH 4 Cl solution and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc), and the resulting solid was washed with hexane to give the title compound (0.625 g) as a white solid.

MS (ESI+): [M+H]+ 279.1.

C) 1-(2-(Cyclopropylcarbonyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (236 mg), (6-bromo-1-methyl-1H-benzimidazol-2-yl)(cyclopropyl)methanone (300 mg), N,N′-dimethylethylenediamine (0.115 ml), copper iodide (205 mg) and potassium carbonate (594 mg) in DMSO (3 ml) was stirred at 150° C. for 1 h. The mixture was purified by NH silica gel column chromatography (hexane/EtOAc). The obtained solid was washed with water and IPE to give the title compound (76 mg) as a yellow solid.

MS (ESI+): [M+H]+ 418.1.

1 H NMR (300 MHz, CDCl 3 ): δ 1.15-1.38 (4H, m), 3.44-3.57 (1H, m), 4.13 (3H, s), 5.03 (2H, s), 6.03-6.12 (2H, m), 7.11 (2H, t, J=8.7 Hz), 7.28-7.34 (2H, m), 7.41 (2H, dd, J=5.3, 8.7 Hz), 7.51 (1H, d, J=1.9 Hz), 7.98 (1H, d, J=8.7 Hz).

4-((5-Chloropyridin-2-yl)methoxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (5-chloropyridin-2-yl)methanol (102 mg) and tributylphosphine (266 μl) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg) at 60° C., and the mixture was stirred at the same temperature for 3 h. The mixture was diluted with EtOAc, and washed with water and brine. The organic layer was concentrated, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (76.8 mg) as a white solid.

MS (ESI+): [M+H]+ 407.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.84-0.96 (4H, m), 2.01-2.12 (1H, m), 2.47 (3H, s), 5.24 (2H, s), 5.99 (1H, d, J=2.6 Hz), 6.18 (1H, dd, J=2.7, 7.6 Hz), 7.11 (1H, dd, J=1.8, 9.5 Hz), 7.43 (1H, d, J=9.5 Hz), 7.61 (1H, d, J=8.3 Hz), 7.68 (1H, d, J=7.7 Hz), 8.03 (1H, dd, J=2.4, 8.3 Hz), 8.37 (1H, s), 8.67 (1H, d, J=2.4 Hz).

1-(2-(Cyclopropyl(methoxy)methyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) 1-(2-(Cyclopropyl(hydroxy)methyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

Sodium borohydride (10.9 mg) was added to a solution of 1-(2-(cyclopropylcarbonyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (60.0 mg) in THF (2 ml)-MeOH (0.2 ml) at room temperature. The mixture was stirred at room temperature for 30 min. The mixture was quenched with water and extracted with EtOAc/THF twice. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The solid was washed with Et 2 O to give the title compound (47.9 mg) as a white solid.

MS (ESI+): [M+H]+ 420.2.

B) 1-(2-(Cyclopropyl(methoxy)methyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

NaH (40% oil dispersion, 5.2 mg) was added to a solution of 1-(2-(cyclopropyl(hydroxy)methyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (30 mg) and iodomethane (0.013 ml) in THF (2 ml)-DMF (1 ml) at room temperature. The mixture was stirred at room temperature for 30 min. The mixture was quenched with water and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The resulting solid was washed with Et 2 O to give the title compound (23.6 mg) as a white solid.

MS (ESI+): [M+H]+ 434.2.

1-(6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarbonitrile

To a solution of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (73 mg), 1-cyanocyclopropanecarboxylic acid (25.1 mg) and N,N-diisopropylethylamine (0.11 ml) in DMF (2 ml) was added HATU (86 mg), and the mixture was stirred at room temperature overnight. The mixture was poured into a mixture of EtOAc and water, and the organic layer was washed with brine, dried over MgSO 4 , and concentrated. Then the resulting residue was heated in AcOH (1 ml) at 90° C. for 1 h. The mixture was concentrated, and poured into saturated NaHCO 3 . The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried over MgSO 4 , concentrated, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (8 mg) as a white solid.

MS (ESI+): [M+H]+ 415.1.

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(tetrahydrofuran-2-yl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and tetrahydrofuran-2-carboxylic acid.

MS (ESI+): [M+H]+ 420.2.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(1-phenylethoxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using 1-phenylethanol and 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one.

MS (ESI+): [M+H]+ 386.2.

4-((4-Chlorobenzyl)oxy)-1-(2-isobutyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) 6-Bromo-2-isobutyl-1-methyl-1H-benzimidazole

To a solution of 5-bromo-N 1 -methylbenzene-1,2-diamine (159 mg), isovaleric acid (0.087 ml) and N,N-diisopropylethylamine (0.41 ml) in DMF (2 ml) was added HATU (316 mg) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl 2 tube) for 3 h. After evaporation of the mixture, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting residue was stirred in AcOH (2.0 ml) at 80° C. for 1 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (156 mg) as a pale yellow solid.

MS (ESI+): [M+H]+ 268.0.

B) 4-((4-Chlorobenzyl)oxy)-1-(2-isobutyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (115 mg), 6-bromo-2-isobutyl-1-methyl-1H-benzimidazole (130 mg), potassium carbonate (202 mg), copper iodide (93 mg), N,N′-dimethylethylenediamine (0.052 ml) and DMSO (3 ml) was heated at 120° C. for 3 h under microwave irradiation. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The precipitate was collected by filtration, and washed with IPE and EtOAc to give the title compound (23 mg) as an off-white solid.

MS (ESI+): [M+H]+ 422.2.

1 H NMR (300 MHz, DMSO-d 6 ): δ 0.98 (6H, d, J=6.8 Hz), 2.21 (1H, dt, J=6.8, 13.6 Hz), 2.77 (2H, d, J=7.2 Hz), 3.75 (3H, s), 5.16 (2H, s), 5.98 (1H, d, J=2.6 Hz), 6.06-6.14 (1H, m), 7.07 (1H, dd, J=1.9, 8.7 Hz), 7.50 (4H, s), 7.53 (1H, d, J=1.9 Hz), 7.60 (2H, dd, J=1.7, 8.1 Hz).

1-(2-(2,2-Difluorocyclopropyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 2,2-difluorocyclopropanecarboxylic acid.

MS (ESI+): [M+H]+ 426.1.

1-(2-Cyclopentyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and cyclopentanecarboxylic acid.

MS (ESI+): [M+H]+ 418.1.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(2,3-dihydro-1H-inden-1-yloxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using 2,3-dihydro-1H-inden-1-ol and 1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one.

MS (ESI+): [M+H]+ 398.2.

4-((4-Fluorobenzyl)oxy)-1-(2-(methoxymethyl)-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

A) (6-Iodo-3-methylimidazo[1,2-a]pyridin-2-yl)methanol

To a stirred solution of ethyl 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylate (2.0 g) in DCM (20 ml) was added diisobutylaluminum hydride (1.76 M solution in toluene, 7.72 ml) at −19° C. The resultant mixture was stirred at the same temperature for 3 h and then at room temperature for 4 h. The reaction mixture was then quenched with MeOH and water at −40° C. The reaction mixture was acidified with few drops of 5 M HCl and poured into saturated NaHCO 3 . The mixture was extracted with EtOAc, and the extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (1.1 g) as a yellow solid.

MS (ESI+): [M+H]+ 288.9.

B) 2-(Chloromethyl)-6-iodo-3-methylimidazo[1,2-a]pyridine

To a stirred solution of (6-iodo-3-methylimidazo[1,2-a]pyridin-2-yl)methanol (200 mg) in DCM (2 ml) was added thionyl chloride (56 μl) at room temperature, and the mixture was stirred for 4 h. Additional thionyl chloride (125 μl) was added to the reaction mixture, and the mixture was stirred for further 3 h. The reaction mixture was diluted with DCM, and washed with saturated NaHCO 3 solution. The DCM layer was separated, dried over Na 2 SO 4 and concentrated in vacuo to give the title compound (150 mg) as a yellow solid.

MS (ESI+): [M+H]+ 306.6.

C) 6-Iodo-2-(methoxymethyl)-3-methylimidazo[1,2-a]pyridine

To a stirred solution of 2-(chloromethyl)-6-iodo-3-methylimidazo[1,2-a]pyridine (150 mg) in MeOH (2.5 ml) was added sodium methoxide (65 mg), and the resulting mixture was heated at reflux for 3 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The mixture was diluted with water, and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (100 mg) as an off-white solid.

MS (ESI+): [M+H]+ 303.0.

D) 4-((4-Fluorobenzyl)oxy)-1-(2-(methoxymethyl)-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 6-iodo-2-(methoxymethyl)-3-methylimidazo[1,2-a]pyridine.

MS (ESI+): [M+H]+ 394.0.

4-((4-Fluorobenzyl)oxy)-1-(3-methyl-2-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

A) 1-(Tetrahydrofuran-3-yl)propan-1-one

To a stirred solution of N-methoxy-N-methyltetrahydrofuran-3-carboxamide (4.1 g) in THF (40 ml) was added ethylmagnesium bromide (3 M in ether, 13.0 ml) at 0° C. The reaction mixture was then slowly warmed to room temperature and stirred for 4 h. The reaction mixture was quenched with saturated 1 M HCl (10 ml), and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The mixture was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (3.0 g) as a pale yellow liquid.

1 H NMR (400 MHz, CDCl 3 ): δ 1.06 (3H, t, J=7.3 Hz), 2.01-2.12 (2H, m), 2.42-2.54 (2H, m), 3.16-3.24 (1H, m), 3.69-3.95 (4H, m).

B) 6-Iodo-3-methyl-2-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridine

To a stirred solution of 1-(tetrahydrofuran-3-yl)propan-1-one (2.8 g) in MeOH (25 ml) was added a solution of bromine (1.12 ml) in MeOH (25 ml) over a period of 2 h, and the mixture was stirred at room temperature for further 4 h. The reaction mixture was then quenched with 0.1 M sodium thiosulfate under ice-cooled condition under stirring. The mixture was extracted with ether, and the extract was washed successively with water and brine, dried over Na 2 SO 4 , and concentrated in vacuo to give the intermediate bromide (1.8 g) as a black oil. A mixture of the intermediate bromide (4.0 g), 2-amino-5-iodopyridine (2.1 g) and EtOH (20 ml) was heated at reflux for 16 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The resulting residue was diluted with EtOAc, washed with water followed by brine. The EtOAc layer was dried over Na 2 SO 4 and concentrated in vacuo. The crude product thus obtained was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (350 mg) as a yellow solid.

MS (ESI+): [M+H]+ 329.0.

C) 4-((4-Fluorobenzyl)oxy)-1-(3-methyl-2-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 6-iodo-3-methyl-2-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridine.

MS (ESI+): [M+H]+ 420.0.

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(2-methylcyclopropyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

HATU (235 mg) was added to a solution of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (200 mg), N,N-diisopropylethylamine (0.308 ml) and 2-methylcyclopropanecarboxylic acid (0.057 ml) in DMF (3 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with brine and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO 4 , and concentrated in vacuo. The resulting residue in AcOH (1 ml) was stirred at 80° C. for 1 h. After evaporation of the solvent, the residue was passed through NH silica pad and concentrated in vacuo. The resulting solid was recrystallized from THF to give the title compound as a white solid.

MS (ESI+): [M+H]+ 404.2.

1 H NMR (300 MHz, CDCl 3 ): δ 0.87-0.99 (1H, m), 1.28 (3H, d, J=6.0 Hz), 1.41 (1H, dt, J=4.5, 8.8 Hz), 1.53-1.64 (1H, m), 1.64-1.74 (1H, m), 3.81 (3H, s), 5.02 (2H, s), 5.97-6.15 (2H, m), 7.00-7.17 (3H, m), 7.28-7.34 (2H, m), 7.41 (2H, dd, J=5.3, 8.7 Hz), 7.69 (1H, d, J=8.7 Hz).

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(trichloromethyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (270 mg) in AcOH (3 ml) was added methyl 2,2,2-trichloroacetimidate (0.196 ml) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. Water was added to the mixture. The resulting precipitate was collected by filtration and dried to give the title compound (220 mg) as an ivory solid.

MS (ESI+): [M+H]+ 466.0.

4-((4-Chlorobenzyl)oxy)-1-(1-methyl-2-(trifluoromethyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) 6-Bromo-1-methyl-2-(trifluoromethyl)-1H-benzimidazole

The mixture of 5-bromo-N 1 -methylbenzene-1,2-diamine (300 mg) and TFA (10 ml) was stirred at 90° C. overnight. The mixture was quenched with saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 , passed through NH silica gel pad and concentrated in vacuo. The precipitate was collected by filtration, washed with IPE/hexane and dried in vacuo to give the title compound (265 mg) as a purple solid.

MS (ESI+): [M+H]+ 280.9.

B) 4-((4-Chlorobenzyl)oxy)-1-(1-methyl-2-(trifluoromethyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one and 6-bromo-1-methyl-2-(trifluoromethyl)-1H-benzimidazole.

MS (ESI+): [M+H]+ 434.1.

4-((4-Chlorobenzyl)oxy)-1-(2-(2-methoxyethyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) N-(5-Bromo-2-nitrophenyl)-3-methoxy-N-methylpropanamide

The title compound was obtained in an analogous manner to step A in example 29 using 5-bromo-N-methyl-2-nitroaniline and 3-methoxypropanoyl chloride.

MS (ESI+): [M+H]+ 319.0.

B) 6-Bromo-2-(2-methoxyethyl)-1-methyl-1H-benzimidazole

The title compound was obtained in an analogous manner to step B in example 29 using N-(5-bromo-2-nitrophenyl)-3-methoxy-N-methylpropanamide.

MS (ESI+): [M+H]+ 270.0.

C) 4-((4-Chlorobenzyl)oxy)-1-(2-(2-methoxyethyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one and 6-bromo-2-(2-methoxyethyl)-1-methyl-1H-benzimidazole.

MS (ESI+): [M+H]+ 424.1.

4-(Benzyloxy)-1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) 6-Bromo-2-ethyl-1-methyl-1H-benzimidazole

A mixture of 5-bromo-N-methyl-2-nitroaniline (10 g), zinc (14.15 g), NH 4 Cl (23.15 g), MeOH (70 ml), 1 M HCl (10 ml) and water (35 ml) was stirred at 50° C. overnight. The mixture was neutralized with saturated NaHCO 3 solution and passed through celite pad to remove the precipitate. After evaporation of the solvent, the mixture was extracted with EtOAc three times. The organic layer was separated, washed with water and brine, dried over MgSO 4 , passed through NH silica pad, and concentrated in vacuo to give an intermediate diamine (8.36 g) as a dark brown oil.

The intermediate diamine was dissolved in DMF (0.160 ml), and N,N-diisopropylethylamine (15.12 ml), propanoic acid (3.53 ml) and HATU (18.1 g) were added. The mixture was stirred at room temperature for 2 h. The mixture was quenched with brine and extracted with EtOAc five times. The organic layer was separated, dried over MgSO 4 and concentrated in vacuo. The resulting residue was dissolved in AcOH (70.0 ml), and stirred at 80° C. for 1 h. After evaporation of the solvent, the residue was passed through NH silica pad and purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was washed with IPE/hexane to give the title compound (5.92 g) as a red solid.

MS (ESI+): [M+H]+ 239.0.

B) 4-(Benzyloxy)-1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 4-benzyloxy-2(1H)-pyridone (1 g), 6-bromo-2-ethyl-1-methyl-1H-benzimidazole (1.19 g), N,N′-dimethylethylenediamine (0.530 ml), copper(I) iodide (0.946 g), potassium carbonate (2.06 g) and DMSO (20 ml) was stirred at 150° C. for 2 h. The mixture was added to 28% NH 3 solution, and the precipitate was collected. The solid was dissolved in THF, passed through NH silica pad and concentrated in vacuo to give the title compound (986 mg) as a pink solid. A part of the target compound was treated with activated carbon and recrystallized from THF to give 46.1 mg of the title compound as a white solid.

MS (ESI+): [M+H]+ 360.4.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.33 (3H, t, J=7.4 Hz), 2.90 (2H, q, J=7.5 Hz), 3.74 (3H, s), 5.16 (2H, s), 5.98 (1H, s), 6.10 (1H, d, J=5.4 Hz), 7.07 (1H, d, J=8.8 Hz), 7.34-7.51 (5H, m), 7.53 (1H, s), 7.55-7.62 (2H, m).

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(2,2,2-trifluoroethyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 3,3,3-trifluoropropanoic acid.

MS (ESI+): [M+H]+ 432.2.

4-[(5-Chlorothiophen-2-yl)methoxy]-1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) 1-(2-Ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one

A mixture of 4-(benzyloxy)-1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (3.5 mg), Pd/C (10%, 700 mg) and MeOH (10 ml) was stirred under H 2 atmosphere at room temperature for 2 h. The insoluble material was removed by filtration, and the filtrate was concentrated to give the title compound (1.6 g) as a white solid.

MS (ESI+): [M+H]+ 270.2.

B) 4-[(5-Chlorothiophen-2-yl)methoxy]-1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a mixture of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (500 mg), (5-chloro-2-thienyl)methanol (552 mg) and tributylphosphine (1.38 ml) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.41 g), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc to MeOH/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (143 mg) as a white solid.

MS (ESI+): [M+H]+ 400.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.33 (3H, t, J=7.4 Hz), 2.90 (2H, q, J=7.5 Hz), 3.74 (3H, s), 5.30 (2H, s), 6.02-6.11 (2H, m), 7.03-7.12 (2H, m), 7.17 (1H, d, J=3.6 Hz), 7.54 (1H, s), 7.59 (2H, d, J=8.5 Hz).

6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-N-(2-hydroxyethyl)-1-methyl-1H-benzimidazole-2-carboxamide

The title compound was obtained in an analogous manner to step A in example 31 using 2-aminoethanol and 4-((4-fluorobenzyl)oxy)-1-(1-methyl-2-(trichloromethyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one.

MS (ESI+): [M+H]+ 437.2.

4-[(5-Chlorothiophen-3-yl)methoxy]-1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a mixture of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (126 mg), (5-chloro-3-thienyl)methanol (139 mg) and tributylphosphine (0.347 ml) in THF (8 ml) was added 1,1′-(azodicarbonyl)dipiperidine (354 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried MgSO 4 , and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc to MeOH/EtOAc). The resulting solid was recrystallized from EtOH/hexane to give the title compound (90 mg) as a white solid.

MS (ESI+): [M+H]+ 400.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.33 (3H, t, J=7.5 Hz), 2.90 (2H, q, J=7.5 Hz), 3.74 (3H, s), 5.06 (2H, s), 5.99 (1H, d, J=2.5 Hz), 6.07 (1H, dd, J=2.6, 7.5 Hz), 7.06 (1H, dd, J=1.8, 8.4 Hz), 7.21 (1H, s), 7.53 (1H, d, J=1.8 Hz), 7.55-7.63 (3H, m).

4-((4-Fluorobenzyl)oxy)-1-(2-(2-fluoropropyl)-1-methyl-1H benzimidazol-6-yl)pyridin-2(1H)-one

A) 4-((4-Fluorobenzyl)oxy)-1-(2-(2-hydroxypropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 3-hydroxybutyric acid.

MS (ESI+): [M+H]+ 408.2.

B) 4-((4-Fluorobenzyl)oxy)-1-(2-(2-fluoropropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

BAST (0.14 ml) was added dropwise to a mixture of 4-((4-fluorobenzyl)oxy)-1-(2-(2-hydroxypropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (78.6 mg) in toluene (1 ml) at room temperature. The mixture was stirred at 80° C. under Ar atmosphere for 5 min. The mixture was quenched with saturated NaHCO 3 solution at room temperature and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc to MeOH/EtOAc). The solid was recrystallized from IPA/hexane to give the title compound (24.6 mg) as a pink solid.

MS (ESI+): [M+H]+ 410.2.

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(4-methyl-1,3-thiazol-5-yl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 4-methyl-1,3-thiazole-5-carboxylic acid.

MS (ESI+): [M+H]+ 447.3.

6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-3-methylimidazo[1,2-a]pyridine-2-carbonitrile

A) 6-Iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid

To a stirred solution of ethyl 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylate (1.5 g) in a mixture of THF (10 ml) and water (10 ml) was added aqueous lithium hydroxide (381 mg), and the resulting mixture was stirred for 16 h at room temperature. The mixture was concentrated in vacuo, and partitioned between EtOAc and water. The organic layer was neutralized with 2 M HCl. The mixture was extracted with EtOAc, dried over Na 2 SO 4 , and concentrated in vacuo to give the title compound (1 g) as a yellow solid.

MS (ESI+): [M+H]+ 302.9.

B) 6-Iodo-3-methylimidazo[1,2-a]pyridine-2-carboxamide

To a stirred solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid (1.0 g) in DMF (15 ml) were added HATU (1.88 g) and triethylamine (1.38 ml) at 0° C. The mixture was allowed to warm to room temperature for 30 min, and then NH 4 Cl (725 mg) was added thereto. The resultant mixture was stirred at the same temperature for 18 h. The mixture was then concentrated in vacuo and diluted with DCM (100 ml). The DCM layer was successively washed with saturated aqueous NH 4 Cl solution, saturated aqueous NaHCO 3 solution, water and brine. The DCM layer was then dried over Na 2 SO 4 and concentrated in vacuo to give the title compound (600 mg) as a yellow solid.

MS (ESI+): [M+H]+ 301.9.

C) 6-Iodo-3-methylimidazo[1,2-a]pyridine-2-carbonitrile

A mixture of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxamide (600 mg) and POCl 3 (40 ml) was heated at reflux for 3 h. The mixture was then cooled to room temperature, and the reaction mixture was concentrated in vacuo. The residue was poured into ice-cold saturated NaHCO 3 solution, and extracted with EtOAc. The extract was washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo to give the title compound (500 mg) as a yellow solid.

MS (ESI+): [M+H]+ 283.9.

D) 6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-3-methylimidazo[1,2-a]pyridine-2-carbonitrile

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carbonitrile.

MS (ESI+): [M+H]+ 375.0.

5-((4-Chlorobenzyl)oxy)-2-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridazin-3(2H)-one

A) 5-((4-Chlorobenzyl)oxy)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one

To a mixture of 5-hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg), 1-bromomethyl-4-chlorobenzene (209 mg), CH 3 CN (8 ml) and DMF (1 ml) was added potassium carbonate (282 mg), and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated in vacuo and diluted with water. The mixture was extracted with EtOAc, and extract was washed successively with water and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was triturated with n-hexane to give the title compound (210 mg) as a white solid.

MS (ESI+): [M+H]+ 321.2.

B) 5-((4-Chlorobenzyl)oxy)pyridazin-3(2H)-one

To a stirred suspension of 5-((4-chlorobenzyl)oxy)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (210 mg) in MeOH (5 ml) was added conc. HCl (0.5 ml) at room temperature, and then the reaction mixture was heated at reflux for 3 h. The mixture was cooled to room temperature, concentrated in vacuo and neutralized with saturated NaHCO 3 (20 ml). The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound (140 mg) as an off-white solid.

MS (ESI+): [M+H]+ 237.2.

C) 5-((4-Chlorobenzyl)oxy)-2-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridazin-3(2H)-one

To a stirred degassed mixture of 5-((4-chlorobenzyl)oxy)pyridazin-3(2H)-one (50 mg), 2-cyclopropyl-6-iodo-3-methylimidazo[1,2-a]pyridine (76 mg), potassium carbonate (88 mg) in dioxane (6 ml) were added copper iodide (8 mg) and trans-N,N′-dimethylcyclohexane-1,2-diamine (6 mg). The reaction vessel was sealed and heated at 110° C. for 16 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The crude residue was diluted with DCM (100 ml), washed with brine (30 ml), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (60 mg) as a white solid.

MS (ESI+): [M+H]+ 407.2.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.88-0.92 (4H, m), 2.06-2.09 (1H, m), 2.47 (3H, s), 5.23 (2H, s), 6.54 (1H, d, J=2.6 Hz), 7.23 (1H, dd, J=1.7, 9.3 Hz), 7.46 (1H, d, J=9.4 Hz), 7.50-7.55 (4H, m), 8.01 (1H, d, J=2.7 Hz), 8.46 (1H, s).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-methyl-2-thienyl)methoxy)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (4-methyl-2-thienyl)methanol (138 mg) and tributylphosphine (322 mg) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg) in dry THF (5 ml). The mixture was stirred under sonication at 60° C. for 2 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM, and the DCM layer was washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (43 mg) as a white solid.

MS (ESI+): [M+H]+ 392.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.03-1.09 (4H, m), 2.21 (3H, s), 2.26-2.28 (1H, m), 3.85 (3H, s), 5.27 (2H, s), 6.02-6.06 (2H, m), 7.04 (1H, dd, J=1.8, 8.5 Hz), 7.08 (1H, s), 7.17 (1H, s), 7.50-7.52 (2H, m), 7.56 (1H, d, J=7.4 Hz).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-methyl-2-thienyl)methoxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one and (5-methyl-2-thienyl)methanol.

MS (ESI+): [M+H]+ 392.0.

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 1-(trifluoromethyl)cyclopropanecarboxylic acid.

MS (ESI+): [M+H]+ 458.2.

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(3,3,3-trifluoropropyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 4,4,4-trifluorobutanoic acid.

MS (ESI+): [M+H]+ 446.2.

1-(2-(3,3-Difluorocyclobutyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 3,3-difluorocyclobutanecarboxylic acid.

MS (ESI+): [M+H]+ 440.2.

1-(2-sec-Butyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 2-methylbutyric acid.

MS (ESI+): [M+H]+ 406.2.

4-((4-Chlorobenzyl)oxy)-1-(2-(2,2-difluorocyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) 6-Bromo-2-(2,2-difluorocyclopropyl)-1-methyl-1H-benzimidazole

A mixture of 5-bromo-N′-methylbenzene-1,2-diamine (300 mg), HATU (567 mg), N,N-diisopropylethylamine (0.255 ml), 2,2-difluorocyclopropanecarboxylic acid (182 mg) and DMF (10 ml) was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 , passed through NH silica gel pad and concentrated in vacuo. The precipitate was washed with IPE/hexane, collected by filtration and dried in vacuo to give the title compound (255 mg) as a yellow solid.

MS (ESI+): [M+H]+ 288.9.

B) 4-((4-Chlorobenzyl)oxy)-1-(2-(2,2-difluorocyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (100 mg), 6-bromo-2-(2,2-difluorocyclopropyl)-1-methyl-1H-benzimidazole (122 mg), potassium carbonate (176 mg), N,N′-dimethylethylenediamine (0.046 ml), copper iodide (81 mg) and DMSO (3 ml) was stirred at 150° C. under Ar atmosphere for 1 h. The mixture was quenched with 28% NH 3 solution and the precipitate was collected by filtration. The solid was dissolved in THF, passed through NH silica gel pad and concentrated in vacuo. The precipitate was recrystallized from EtOAc/MeOH to give the title compound (2 mg) as a pale orange solid.

MS (ESI+): [M+H]+ 442.1.

1 H NMR (300 MHz, CDCl 3 ): δ 1.99-2.15 (1H, m), 2.43-2.57 (1H, m), 2.87 (1H, td, J=7.6, 11.0 Hz), 3.84 (3H, s), 5.03 (2H, s), 6.03-6.10 (2H, m), 7.16 (1H, dd, J=1.9, 8.7 Hz), 7.28-7.44 (6H, m), 7.79 (1H, d, J=8.7 Hz).

1-(2-Ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (90 mg), HATU (106 mg), propionic acid (0.040 ml), N,N-diisopropylethylamine (0.136 ml) and DMF (2 ml) was stirred at room temperature under a dry atmosphere (CaCl 2 tube) for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The resulting residue was dissolved in AcOH (2 ml), and the mixture was stirred at 90° C. for 1 h. After evaporation of the solvent, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOAc/MeOH to give the title compound (44.9 mg) as an off-white solid.

MS (ESI+): [M+H]+ 378.2.

1 H NMR (300 MHz, CDCl 3 ): δ 1.33 (3H, t, J=7.4 Hz), 2.90 (2H, q, J=7.6 Hz), 3.74 (3H, s), 5.13 (2H, s), 5.99 (1H, d, J=2.6 Hz), 6.09 (1H, dd, J=2.8, 7.7 Hz), 7.06 (1H, dd, J=1.9, 8.3 Hz), 7.21-7.31 (2H, m), 7.49-7.56 (3H, m), 7.59 (2H, dd, J=2.1, 8.1 Hz).

1-(2-Ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (5 g), 6-bromo-2-ethyl-1-methyl-1H-benzimidazole (6.54 g), potassium carbonate (9.46 g), N,N′-dimethylethylenediamine (2.91 ml), copper iodide (1.3 g) and DMSO (100 ml) was stirred at 150° C. for 4 h. After cooling, the mixture was poured into 28% NH 3 solution at 0° C. The precipitate was collected by filtration and dissolved in EtOAc/THF. The resulting solution was washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was treated with activated carbon in MeOH, and recrystallized from MeOH/water to give the title compound (3.44 g) as a white solid.

MS (ESI+): [M+H]+ 378.2.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.33 (3H, t, J=7.5 Hz), 2.90 (2H, q, J=7.4 Hz), 3.74 (3H, s), 5.13 (2H, s), 5.99 (1H, d, J=2.5 Hz), 6.09 (1H, dd, J=2.6, 7.6 Hz), 7.06 (1H, dd, J=1.6, 8.3 Hz), 7.26 (2H, t, J=8.8 Hz), 7.48-7.56 (3H, m), 7.59 (2H, dd, J=3.0, 8.0 Hz).

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-propyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (90 mg), HATU (106 mg), n-butyric acid (0.024 ml), N,N-diisopropylethylamine (0.136 ml) and DMF (2 ml) was stirred at room temperature under a dry atmosphere (CaCl 2 tube) for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The resulting residue was dissolved in AcOH (2.0 ml) and stirred at 90° C. for 1 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOAc/MeOH to give the title compound (48.7 mg) as an off-white solid.

MS (ESI+): [M+H]+ 392.2.

1 H NMR (300 MHz, CDCl 3 ): δ 1.00 (3H, t, J=7.4 Hz), 1.74-1.88 (2H, m), 2.86 (2H, t, J=7.6 Hz), 3.74 (3H, s), 5.13 (2H, s), 5.98 (1H, s), 6.09 (1H, dd, J=3.0, 7.6 Hz), 7.06 (1H, dd, =2.1, 8.5 Hz), 7.21-7.31 (2H, m), 7.50-7.56 (3H, m), 7.56-7.61 (2H, m).

1-(2-(4,5-Dihydro-1,3-oxazol-2-yl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

Thionyl chloride (0.078 ml) was added to a mixture of 6-(4-((4-fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-N-(2-hydroxyethyl)-1-methyl-1H-benzimidazole-2-carboxamide (50.0 mg) in THF (2 ml) at room temperature. The mixture was stirred at room temperature for 3 h, and at 50° C. under Ar atmosphere for 2 h. After evaporation of the solvent, THF (2 ml) was added to the residue. NaH (40% oil dispersion, 34.3 mg) was added to the mixture at 0° C. The mixture was stirred at room temperature for 1 h, and at 50° C. under Ar atmosphere for 2 h. After addition of water (0.5 ml), the mixture was stirred at room temperature over weekend. The mixture was quenched with brine and extracted with EtOAc/THF. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The solid was washed with EtOAc to give the title compound (17.9 mg) as a white solid.

MS (ESI+): [M+H]+ 419.2.

1-(2-Acetyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) 1-(6-Bromo-1-methyl-1H-benzimidazol-2-yl)ethanone

Methylmagnesium chloride (1.0 M in THF, 4.70 ml) was added dropwise to a solution of 6-bromo-N-methoxy-N,1-dimethyl-1H-benzimidazole-2-carboxamide (700 mg) in THF (10 ml) at 0° C. The mixture was stirred at 0° C. under Ar atmosphere for 30 min. The mixture was quenched with saturated NH 4 Cl solution and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated ao in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc), and the resulting solid was washed with IPE to give the title compound (360 mg) as a white solid.

MS (ESI+): [M+H]+ 253.0.

B) 1-(2-Acetyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (312 mg), 1-(6-bromo-1-methyl-1H-benzimidazol-2-yl)ethanone (360 mg), N,N′-dimethylethylenediamine (0.141 ml), copper iodide (250 mg) and potassium carbonate (393 mg) in DMSO (3 ml) was stirred at 150° C. for 1 h. The mixture was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH/IPA to give the title compound (54.6 mg) as a pale orange solid.

MS (ESI+): [M+H]+ 392.2.

1 H NMR (300 MHz, CDCl 3 ): δ 2.85 (3H, s), 4.13 (3H, s), 5.03 (2H, s), 6.04-6.21 (2H, m), 7.11 (2H, t, J=8.7 Hz), 7.22-7.34 (2H, m), 7.41 (2H, dd, J=5.3, 8.7 Hz), 7.51 (1H, d, J=1.9 Hz), 7.97 (1H, d, J=8.7 Hz).

4-(Benzyloxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one hydrochloride

To a suspension of 4-(benzyloxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (50 mg) in EtOAc (3 ml) was added 4 M HCl (EtOAc solution) (0.067 ml), and the mixture was stirred at room temperature for 3 h. The resulting solid was collected, washed with EtOAc, and dried in vacuo to give the title compound (44.0 mg) as a white solid.

MS (ESI+): [M+H]+ 372.2.

1 H NMR (300 MHz, DMSO-d 6 ): δ 0.92-1.15 (4H, m), 2.16-2.30 (1H, m), 2.55 (3H, s), 5.18 (2H, s), 6.05 (1H, d, J=2.6 Hz), 6.22 (1H, dd, J=2.6, 7.6 Hz), 7.33-7.51 (5H, m), 7.64-7.79 (3H, m), 8.81 (1H, brs).

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-((2,2,2-trifluoroethoxy)methyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and (2,2,2-trifluoroethoxy)acetic acid.

MS (ESI+): [M+H]+ 462.2.

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(1,3-oxazol-5-yl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (100 mg), oxazole-5-carboxylic acid (33.3 mg), HATU (118 mg), N,N-diisopropylethylamine (0.154 ml) and DMF (2 ml) was stirred at room temperature for 2 h. The mixture was poured into saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The resulting residue was dissolved in AcOH (2 ml), and the mixture was stirred at 80° C. for 2 h. The mixture was concentrate in vacuo. The residue was purified by NH silica gel column chromatography (MeOH/EtOAc). The resulting solid was washed with EtOAc/hexane to give the title compound (40.7 mg) as an off-white solid.

MS (ESI+): [M+H]+ 417.2.

1 H NMR (300 MHz, DMSO-d 6 ): δ 4.03 (3H, s), 5.15 (2H, s), 6.01 (1H, d, J=2.6 Hz), 6.12 (1H, dd, J=2.6, 7.6 Hz), 7.18-7.32 (3H, m), 7.54 (2H, dd, J=5.3, 8.7 Hz), 7.64 (1H, d, J=7.6 Hz), 7.70-7.80 (2H, m), 8.02 (1H, s), 8.72 (1H, s).

4-((4-Chlorobenzyl)oxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyrimidin-2(1H)-one

A) 2-Chloro-4-((4-chlorobenzyl)oxy)pyrimidine

To a stirred solution of 2,4-dichloropyrimidine (10.4 g) and (4-chlorophenyl)methanol (10 g) in DMF (50 ml) was added potassium carbonate (14.5 g), and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with water while the product was precipitated out from the reaction medium. The precipitate was collected by filtration and dried under vacuum to give the title compound (4.8 g) as an off-white solid.

MS (ESI+): [M+H]+ 255.2.

B) 4-((4-Chlorobenzyl)oxy)pyrimidin-2(1H)-one

To a stirred solution of 2-chloro-4-((4-chlorobenzyl)oxy)pyrimidine (2.8 g) in dioxane and water (1:4, 30 ml) was added NaOH (440 mg), and the mixture was heated at reflux for 3 h. The reaction mixture was then cooled to 0° C. and the product was precipitated out from the reaction medium. The precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound (130 mg) as an off-white solid.

MS (ESI+): [M+H]+ 237.2.

C) 4-((4-Chlorobenzyl)oxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyrimidin-2(1H)-one

To a stirred degassed mixture of 4-((4-chlorobenzyl)oxy)pyrimidin-2(1H)-one (130 mg), 2-cyclopropyl-6-iodo-3-methylimidazo[1,2-a]pyridine (180 mg), potassium carbonate (228 mg) and dry dioxane (8 ml) were added copper iodide (41.8 mg) and trans-N,N′-dimethylcyclohexane-1,2-diamine (32 mg). The reaction vessel was sealed and heated at 110° C. for 16 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The crude residue was diluted with DCM, and the DCM layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (40 mg) as an off-white solid.

MS (ESI+): [M+H]+ 407.2.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.85-0.92 (4H, m), 2.05-2.09 (1H, m), 2.47 (3H, s), 5.40 (2H, s), 6.21 (1H, d, J=7.2 Hz), 7.19 (1H, dd, J=1.6, 9.5 Hz), 7.44-7.52 (5H, m), 8.11 (1H, d, J=7.2 Hz), 8.47 (1H, s).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((2-fluorobenzyl)oxy)pyridin-2(1H)-one

A) 1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one

To a stirred solution of 4-(benzyloxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (840 mg) in TFA (21 ml) was added anisole (7 ml), and the reaction mixture was heated at 130° C. for 4 h. The mixture was cooled and concentrated in vacuo. The residue was triturated with Et 2 O to give the title compound (778 mg) as a white solid.

MS (ESI+): [M+H]+ 282.0.

B) 1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((2-fluorobenzyl)oxy)pyridin-2(1H)-one

To a stirred suspension of NaH (40% oil dispersion, 50 mg) in THF (9 ml) was added a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg) in THF (1 ml) at 0° C., and then the mixture was stirred at room temperature for 30 min. 1-Bromomethyl-2-fluorobenzene (150 mg) in THF (0.5 ml) was added, and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with ice-water and extracted with DCM. The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) followed by crystallization with DCM/hexane (19:1, 2 ml) to give the title compound (56 mg) as a white solid.

MS (ESI+): [M+H]+ 390.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.04-1.11 (4H, m), 2.24-2.28 (1H, m), 3.85 (3H, s), 5.18 (2H, s), 6.03-6.09 (2H, m), 7.04 (1H, dd, J=1.6, 8.5 Hz), 7.26-7.31 (2H, m), 7.44-7.52 (3H, m), 7.57-7.60 (2H, m).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((3-fluorobenzyl)oxy)pyridin-2(1H)-one

To a stirred suspension of NaH (40% oil dispersion, 50 mg) in THF (9 ml) was added a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg) in THF (1 ml) at 0° C., and then the mixture was stirred at room temperature for 30 min. 1-Bromomethyl-3-fluorobenzene (150 mg) in THF (0.5 ml) was added, and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with ice-water and extracted with DCM. The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) followed by crystallization with DCM/hexane to give the title compound (49 mg) as a white solid.

MS (ESI+): [M+H]+ 390.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.02-1.11 (4H, m), 2.24-2.28 (1H, m), 3.85 (3H, s), 5.18 (2H, s), 5.96 (1H, d, J=2.5 Hz), 6.11 (1H, dd, J=2.5, 7.6 Hz), 7.05 (1H, dd, J=1.5, 8.6 Hz), 7.20 (1H, m), 7.31 (2H, d, J=7.7 Hz), 7.45-7.52 (3H, m), 7.58 (1H, d, J=7.6 Hz).

(6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-3-methylimidazo[1,2-a]pyridin-2-yl)acetonitrile

A) 4-((4-Fluorobenzyl)oxy)-1-(2-(hydroxymethyl)-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and (6-iodo-3-methylimidazo[1,2-a]pyridin-2-yl)methanol.

MS (ESI+): [M+H]+ 380.0.

B) 1-(2-(Chloromethyl)-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

To a stirred solution of 4-((4-fluorobenzyl)oxy)-1-(2-(hydroxymethyl)-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (120 mg) in DCM (1 ml) was added thionyl chloride (1 ml), and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, diluted with DCM and quenched with aqueous NaHCO 3 under ice-cold condition. The organic layer was separated, washed successively with water and brine, dried over Na 2 SO 4 and concentrated in vacuo to give the title compound (120 mg) as an off-white solid.

MS (ESI+): [M+H]+ 398.2.

C) (6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-3-methylimidazo[1,2-a]pyridin-2-yl)acetonitrile

To a stirred solution of 1-(2-(chloromethyl)-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (150 mg) in THF (5 ml) were added trimethylsilyl cyanide (115 μl) and TBAF (1 M in THF, 1.13 ml) at room temperature, and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was then quenched with saturated FeSO 4 , and the organic layer was extracted with DCM. The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (60 mg) as a white solid.

MS (ESI+): [M+H]+ 389.4.

Methyl(1RS,2RS)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate

A) 4-((4-Chlorobenzyl)oxy)-1-(3-(methylamino)-4-nitrophenyl)pyridin-2(1H)-one

A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (10 g), 5-bromo-N-methyl-2-nitroaniline (9.80 g), N,N′-dimethylethylenediamine (4.76 ml), copper iodide (8.08 g), potassium carbonate (17.59 g) and DMSO (200 ml) was heated at 150° C. for 2 h. The mixture was poured into 28% NH 3 solution. The resulting precipitate was collected and washed with IPA. The solid was dissolved in DMSO (100 ml) at 80° C., and allowed to cool to room temperature to give a precipitate. After filtration, the precipitate was washed with IPA and dried to give the title compound (12 g) as a yellow solid.

MS (ESI+): [M+H]+ 386.0.

B) 1-(4-Amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one

Zinc (20.34 g) was added to a suspension of 4-((4-chlorobenzyl)oxy)-1-(3-(methylamino)-4-nitrophenyl)pyridin-2(1H)-one (12 g) in AcOH (200 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was neutralized with saturated NaHCO 3 at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (MeOH/EtOAc) to give the title compound (5.5 g) as a pale orange solid.

MS (ESI+): [M+H]+ 356.2.

C) Methyl(1RS,2RS)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one and (1RS,2RS)-2-(methoxycarbonyl)cyclopropanecarboxylic acid.

MS (ESI+): [M+H]+ 464.2.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(3-thienylmethoxy)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), 3-thienylmethanol (67 μl) and tributylphosphine (258 μl) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (264 mg). The mixture was stirred under sonication at 50° C. for 1 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The crude residue was diluted with DCM (100 ml), and the DCM layer was washed with water (100 ml), brine (30 ml), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (50 mg) as an off-white solid.

MS (ESI+): [M+H]+ 378.2.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.02-1.09 (4H, m), 2.24-2.28 (1H, m), 3.85 (3H, s), 5.13 (2H, s), 5.99 (1H, d, J=2.6 Hz), 6.06 (1H, dd, J=2.6, 7.5 Hz), 7.04 (1H, dd, J=1.7, 8.4 Hz), 7.19 (1H, d, J=4.2 Hz), 7.50-7.52 (2H, m), 7.56-7.60 (2H, m), 7.64 (1H, m).

6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-N,N,3-trimethylimidazo[1,2-a]pyridine-2-carboxamide

A) 6-Iodo-N,N,3-trimethylimidazo[1,2-a]pyridine-2-carboxamide

To a stirred solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid (150 mg) in DMF (5 ml) were added HATU (283 mg) and N,N-diisopropylethylamine (0.17 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 30 min. Dimethylamine (2 M in THF, 0.2 ml) was added, and the resultant mixture was stirred at the same temperature for 18 h. The mixture was then concentrated in vacuo and the residue was diluted with DCM (100 ml). The DCM layer was successively washed with saturated aqueous NH 4 Cl solution (40 ml), saturated aqueous NaHCO 3 solution (20 ml), water (30 ml) and brine (50 ml). The DCM layer was then dried m over Na 2 SO 4 , and concentrated in vacuo to give the title compound (150 mg) as a brown oil.

MS (ESI+): [M+H]+ 329.8.

B) 6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-N,N,3-trimethylimidazo[1,2-a]pyridine-2-carboxamide

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 6-iodo-N,N,3-trimethylimidazo[1,2-a]pyridine-2-carboxamide.

MS (ESI+): [M+H]+ 421.4.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-methoxybenzyl)oxy)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (4-methoxy-phenyl)-methanol (98 mg) and tributylphosphine (320 μl) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg). The mixture was stirred under sonication at 50° C. for 1 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The crude residue was diluted with DCM (100 ml), and the DCM layer was washed with water (50 ml) and brine (30 ml), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (45 mg) as an off-white solid.

MS (ESI+): [M+H]+ 402.2.

1 H NMR (400 MHz, DMSO-d 5 ): δ 1.03-1.09 (4H, m), 2.24-2.28 (1H, s), 3.77 (3H, s), 3.84 (3H, s), 5.05 (2H, s), 5.97 (1H, d, J=2.5 Hz), 6.06 (1H, dd, J=2.6, 7.5 Hz), 6.97 (2H, d, J=8.5 Hz), 7.03 (1H, dd, J=1.7, 8.4 Hz), 7.40 (2H, d, J=8.5 Hz), 7.51 (2H, m), 7.55 (1H, d, J=7.6 Hz).

4-((4-Fluorobenzyl)oxy)-1-(2-(fluoromethyl)-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

A) 2-(Fluoromethyl)-6-iodo-3-methylimidazo[1,2-a]pyridine

To a stirred solution of (6-iodo-3-methylimidazo[1,2-a]pyridin-2-yl)methanol (600 mg) in DCM (2 ml) was added DAST (500 mg) at −78° C. The reaction mixture was then allowed slowly to warm up to room temperature, and stirred at the same temperature for 16 h. The reaction mixture was then diluted with DCM (100 ml), washed with saturated NaHCO 3 solution (100 ml), and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (280 mg) as an off-white solid.

MS (ESI+): [M+H]+ 290.8.

B) 4-((4-Fluorobenzyl)oxy)-1-(2-(fluoromethyl)-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 2-(fluoromethyl)-6-iodo-3-methylimidazo[1,2-a]pyridine.

MS (ESI+): [M+H]+ 382.0.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(1,3-thiazol-2-ylmethoxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one and thiazol-2-ylmethanol.

MS (ESI+): [M+H]+ 379.4.

((4-Chlorobenzyl)oxy)-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) Methyl(1RS,2SR)-2-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate

HATU (554 mg) was added to a solution of 5-bromo-N 1 -methylbenzene-1,2-diamine (279 mg), N,N-diisopropylethylamine (0.727 ml) and (1RS,2SR)-2-(methoxycarbonyl)cyclopropanecarboxylic acid (200 mg) in DMF (5 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was dissolved in AcOH (5 ml), and the mixture was stirred at 80° C. for 1 h. After concentration of the mixture, the residue was neutralized with saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/EtOAc) to give the title compound (80 mg) as an off-white solid.

MS (ESI+): [M+H]+ 309.1.

B) 2-((1RS,2SR)-2-(6-Bromo-1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)propan-2-ol

Methylmagnesium chloride (0.69 ml) was added to a solution of methyl(1RS,2SR)-2-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate (80 mg) in THF (2 ml) at 0° C. The mixture was stirred at room temperature for 3 h. The mixture was quenched with 1 M HCl at room temperature and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO 3 solution and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (34 mg) as a white solid.

MS (ESI+): [M+H]+ 309.2.

C) 4-((4-Chlorobenzyl)oxy)-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (27 mg), 2-((1RS,2SR)-2-(6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)propan-2-ol (35 mg), copper iodide (21.8 mg), N,N′-dimethylethylenediamine (10.1 mg), potassium carbonate (31.7 mg) and DMSO (1 ml) was stirred at 150° C. overnight. The mixture was quenched with 28% NH 3 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (MeOH/EtOAc) to give the title compound (10 mg) as a pale yellow solid.

MS (ESI+): [M+H]+ 464.2.

1 H NMR (300 MHz, CDCl 3 ): δ 1.28 (3H, s), 1.35 (3H, s), 1.49-1.75 (3H, m), 2.03 (1H, td, J=6.4, 8.7 Hz), 3.83 (3H, s), 5.03 (2H, s), 6.00-6.14 (2H, m), 7.11 (1H, dd, J=1.9, 8.3 Hz), 7.27-7.33 (1H, m), 7.34-7.46 (5H, m), 7.64 (1H, d, J=8.3 Hz).

4-((4-Chlorobenzyl)oxy)-1-(2-((1RS,2RS)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

Methylmagnesium chloride (0.575 ml) was added to a solution of methyl(1RS,2RS)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate in THF (2 ml) at 0° C. The mixture was stirred at room temperature for 3 h. The mixture was quenched with 1 M HCl at room temperature and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO 3 solution and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (55 mg) as a white solid.

MS (ESI+): [M+H]+ 464.2.

(1RS,2RS)-2-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylic acid

Sodium hydroxide (1.811 ml) was added to a solution of methyl(1RS,2RS)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1 (2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate (280 mg) in THF (3 ml)-MeOH (3 ml) at room temperature. The mixture was neutralized with 1 M HCl at 0° C. and extracted with EtOAc and MeOH. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The resulting solid was washed with IPE and dried to give the title compound (220 mg) as a white solid.

MS (ESI+): [M+H]+ 450.2.

(1RS,2RS)-2-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxamide

To a solution of (1RS,2RS)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylic acid (150 mg) and triethylamine (0.139 ml) in acetone (2 ml) was added ethyl chloroformate (0.096 ml) at 0° C. The mixture was stirred at 0° C. for 1 h and then NH 3 solution (0.101 ml) was added dropwise. The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/EtOAc) to give the title compound (125 mg) as a white solid.

MS (ESI+): [M+H]+ 449.2.

4-((4-Chlorobenzyl)oxy)-1-(2-cyclopropyl-4-fluoro-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) N-(4-Bromo-2,6-difluorophenyl)cyclopropanecarboxamide

Cyclopropanecarbonyl chloride (1.05 ml) was added to a solution of 4-bromo-2,6-difluoroaniline (1.00 g) and triethylamine (1.61 ml) in THF (10 ml) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with brine and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO 4 , passed through NH silica gel pad and concentrated in vacuo. The solid was washed with IPE/hexane to give the title compound (1.08 g) as a white solid.

1 H NMR (300 MHz, CDCl 3 ): δ 0.76-0.97 (2H, m), 1.07-1.20 (2H, m), 1.45-1.68 (1H, m), 6.82 (1H, br. s.), 7.06-7.19 (2H, m).

B) 6-Bromo-2-cyclopropyl-4-fluoro-1-methyl-1H-benzimidazole

Thionyl chloride (3.17 ml) was added to a solution of N-(4-bromo-2,6-difluorophenyl)cyclopropanecarboxamide (600 mg) at room temperature. The mixture was stirred at 80° C. for 2 h. After evaporation of thionyl chloride, methylamine (36% in MeOH, 4.93 ml) was added. The mixture was stirred at room temperature for 30 min. After evaporation of the solvent and addition of water, the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. To the resulting residue in DMF (2 ml), potassium tert-butoxide (488 mg) was added. The mixture was stirred at 100° C. for 2 h. The mixture was quenched with brine and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (66.8 mg) as a yellow solid.

MS (ESI+): [M+H]+ 269.0.

6-Bromo-4-tert-butoxy-2-cyclopropyl-1-methyl-1H-benzimidazole (103 mg) was also obtained as a byproduct.

MS (ESI+): [M+H]+ 323.2.

C) 4-((4-Chlorobenzyl)oxy)-1-(2-cyclopropyl-4-fluoro-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one and 6-bromo-2-cyclopropyl-4-fluoro-1-methyl-1H-benzimidazole.

MS (ESI+): [M+H]+ 424.1.

1-(4-tert-Butoxy-2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one and 6-bromo-4-tert-butoxy-2-cyclopropyl-1-methyl-1H-benzimidazole.

MS (ESI+): [M+H]+ 478.1.

(1RS,2RS)-2-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarbonitrile

Trifluoroacetic anhydride (0.109 ml) was added to a solution of (1RS,2RS)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxamide (117 mg) and pyridine (0.063 ml) in THF (3 ml) at 0° C. The mixture was stirred at 0° C. under Ar atmosphere for 1 h. The mixture was quenched with saturated NaHCO 3 solution at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The resulting solid was crystallized from THF/hexane to give the title compound (15 mg) as an off-white solid.

MS (ESI+): [M+H]+ 431.2.

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(3-methyl-1,2-oxazol-5-yl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 3-methyl-1,2-oxazole-5-carboxylic acid.

MS (ESI+): [M+H]+ 431.2.

1-(2-(1,5-Dimethyl-1H-pyrazol-3-yl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid.

MS (ESI+): [M+H]+ 444.2.

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(4-methyl-1,3-oxazol-5-yl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (100 mg), 4-methyl-1,3-oxazole-5-carboxylic acid (37.5 mg), HATU (118 mg) and N,N-diisopropylethylamine (0.154 ml) in DMF (2 ml) was stirred at room temperature for 2 h. The mixture was poured into saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The resulting residue was dissolved in AcOH (2 ml), and the mixture was stirred at 80° C. for 2 h. The mixture was concentrate in vacuo, and purified by NH silica gel column chromatography (MeOH/EtOAc). The resulting solid was washed with EtOAc/hexane to give the title compound (63.4 mg) as a white solid.

MS (ESI+): [M+H]+ 431.2.

1 H NMR (300 MHz, DMSO-d 6 ): δ 2.54 (3H, s), 4.01 (3H, s), 5.15 (2H, s), 6.01 (1H, d, J=2.6 Hz), 6.08-6.17 (1H, m), 7.21 (1H, dd, J=2.1, 8.5 Hz), 7.26 (2H, t, J=8.9 Hz), 7.54 (2H, dd, J=5.7, 8.7 Hz), 7.63 (1H, d, J=7.6 Hz), 7.71-7.79 (2H, m), 8.60 (1H, s).

4-((4-Chlorobenzyl)oxy)-1-(1-methyl-2-(2-methylcyclopropyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of HATU (101 mg), 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (90 mg), N,N-diisopropylethylamine (0.130 ml), 2-methylcyclopropanecarboxylic acid (0.049 ml) and DMF (2 ml) was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was dissolved in AcOH (2.00 ml), and the mixture was stirred at 90° C. for 2 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (3 mg) as a diastereomeric mixture. The filtrate was concentrated in vacuo and the precipitate was recrystallized from THF to give the title compound (17 mg) as a diastereomeric mixture.

MS (ESI+): [M+H]+ 420.2.

1 H NMR (300 MHz, CDCl 3 ): δ 0.78-0.97 (1H, m), 1.18-1.29 (4H, m), 1.35-1.48 (1H, m), 1.99 (1H, dt, J=4.4, 8.2 Hz), 3.79-3.87 (3H, m), 5.16 (2H, s), 5.97 (1H, d, J=2.6 Hz), 6.06-6.13 (1H, m), 6.99-7.07 (1H, m), 7.45-7.54 (6H, m), 7.58 (1H, d, J=7.6 Hz).

4-((4-Chlorobenzyl)oxy)-1-(2-(cyclopropylmethyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (90 mg), HATU (101 mg), N,N-diisopropylethylamine (0.130 ml), cyclopropylacetic acid (0.024 ml) and DMF (2 ml) was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was dissolved in AcOH (2.00 ml), and the mixture was stirred at 90° C. for 2 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (56.3 mg) as an off-white solid.

MS (ESI+): [M+H]+ 420.2.

1 H NMR (300 MHz, CDCl 3 ): δ 0.22-0.31 (2H, m), 0.48-0.57 (2H, m), 1.12-1.27 (1H, m), 2.85 (2H, d, J=6.8 Hz), 3.76 (3H, s), 5.16 (2H, s), 5.97 (1H, d, J=2.6 Hz), 6.10 (1H, dd, J=2.8, 7.7 Hz), 7.04-7.11 (1H, m), 7.50 (4H, s), 7.53 (1H, d, J=1.9 Hz), 7.60 (2H, dd, J=2.6, 7.9 Hz).

1-(2-(2,2-Dimethylcyclopropyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 2,2-dimethylcyclopropanecarboxylic acid.

MS (ESI+): [M+H]+ 418.2.

4-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)-2-methylbutanenitrile

A) Methyl 4-(6-bromo-1-methyl-1H-benzimidazol-2-yl)butanoate

The title compound was obtained in an analogous manner to step C in example 13 using 5-bromo-N′-methylbenzene-1,2-diamine and 5-methoxy-5-oxopentanoic acid.

1 H NMR (300 MHz, CDCl 3 ): δ 2.11-2.27 (2H, m), 2.46-2.56 (2H, m), 2.89-2.98 (2H, m), 3.66 (3H, s), 3.72 (3H, s), 7.33 (1H, dd, J=1.5, 8.3 Hz), 7.45 (1H, d, J=1.5 Hz), 7.56 (1H, d, J=8.3 Hz).

B) Methyl 4-(6-bromo-1-methyl-1H-benzimidazol-2-yl)-2-methylbutanoate

Lithium bis(trimethylsilyl)amide (1.6 M in THF, 6.15 ml) was added to a solution of methyl 4-(6-bromo-1-methyl-1H-benzimidazol-2-yl)butanoate (1.02 g) in THF (20 ml) at −78° C. After being stirred at −78° C. for 30 min, iodomethane (0.612 ml) was added to the reaction mixture. The mixture was stirred at room temperature under Ar atmosphere for 2 h. The mixture was quenched with saturated NH 4 Cl solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO 3 solution and brine, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (440 mg) as a pale yellow solid.

MS (ESI+): [M+H]+ 325.1.

C) 4-(6-Bromo-1-methyl-1H-benzimidazol-2-yl)-2-methylbutanoic acid

The title compound was obtained in an analogous manner to example 82 using methyl 4-(6-bromo-1-methyl-1H-benzimidazol-2-yl)-2-methylbutanoate.

MS (ESI+): [M+H]+ 312.0.

D) 4-(6-Bromo-1-methyl-1H-benzimidazol-2-yl)-2-methylbutanamide

The title compound was obtained in an analogous manner to example 83 using 4-(6-bromo-1-methyl-1H-benzimidazol-2-yl)-2-methylbutanoic acid.

MS (ESI+): [M+H]+ 311.0.

E) 4-(6-Bromo-1-methyl-1H-benzimidazol-2-yl)-2-methylbutanenitrile

The title compound was obtained in an analogous manner to example 86 using 4-(6-bromo-1-methyl-1H-benzimidazol-2-yl)-2-methylbutanamide.

1 H NMR (300 MHz, CDCl 3 ): δ 1.37-1.46 (3H, m), 2.08-2.25 (1H, m), 2.26-2.42 (1H, m), 2.86-2.99 (1H, m), 3.00-3.16 (2H, m), 3.73 (3H, s), 7.35 (1H, dd, J=1.9, 8.7 Hz), 7.47 (1H, d, J=1.7 Hz), 7.56 (1H, d, J=8.7 Hz).

F) 4-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)-2-methylbutanenitrile

The title compound was obtained in an analogous manner to step C in example 5 using 4-(6-bromo-1-methyl-1H-benzimidazol-2-yl)-2-methylbutanenitrile and 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one.

MS (ESI+): [M+H]+ 447.1.

6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-N,3-dimethylimidazo[1,2-a]pyridine-2-carboxamide

A) 6-Iodo-N,3-dimethylimidazo[1,2-a]pyridine-2-carboxamide

The title compound was obtained in an analogous manner to step A in example 76 using 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid and methylamine.

MS (ESI+): [M+H]+ 316.2.

B) 6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-N,3-dimethylimidazo[1,2-a]pyridine-2-carboxamide

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 6-iodo-N,3-dimethylimidazo[1,2-a]pyridine-2-carboxamide.

MS (ESI+): [M+H]+ 407.4.

1-(2-Acetyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) 6-Iodo-N-methoxy-N,3-dimethylimidazo[1,2-a]pyridine-2-carboxamide

The title compound was obtained in an analogous manner to step A in example 76 using 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid and N,0-dimethylhydroxylamine hydrochloride.

MS (ESI+): [M+H]+ 345.6.

B) 6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-N-methoxy-N,3-dimethylimidazo[1,2-a]pyridine-2-carboxamide

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridine-2(1H)-one and 6-iodo-N-methoxy-N,3-dimethylimidazo[1,2-a]pyridine-2-carboxamide.

MS (ESI+): [M+H]+ 437.4.

C) 1-(2-Acetyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

To a stirred solution of 6-(4-((4-fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-N-methoxy-N,3-dimethylimidazo[1,2-a]pyridine-2-carboxamide (150 mg) in THF (10 ml) was added methylmagnesium bromide (3 M ether solution, 344 μl) at −78° C., and the resulting mixture was stirred at the same temperature for 2 h. The reaction mixture was then quenched with saturated aqueous NH 4 Cl (40 ml) at −78° C., and slowly warmed to room temperature. The reaction mixture was concentrated in vacuo and diluted with EtOAc (100 ml). The EtOAc layer was washed with brine (40 ml), dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (55 mg) as a white solid.

MS (ESI+): [M+H]+ 392.0.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(1,3-thiazol-5-ylmethoxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one and thiazol-5-yl-methanol.

MS (ESI+): [M+H]+ 379.0.

1-(2-(Cyclopropylcarbonyl)-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 95 using 6-(4-((4-fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-N-methoxy-N,3-dimethylimidazo[1,2-a]pyridine-2-carboxamide and cyclopropylmagnesium bromide.

MS (ESI+): [M+H]+ 418.0.

1-(2-(Difluoromethyl)-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) 6-Iodo-3-methylimidazo[1,2-a]pyridine-2-carbaldehyde

To a stirred solution of ethyl 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylate (1.0 g) in DCM (20 ml) was added a solution of diisobutylaluminum hydride (1.0 M toluene solution, 3.7 ml) at −78° C. The resultant mixture was stirred at the same temperature for 2 h. The reaction mixture was then quenched with a mixture of MeOH (2 ml) and water (2 ml) at −78° C. This reaction mixture was then acidified with a few drops of 5 M HCl, and washed with saturated NaHCO 3 solution (20 ml). The mixture was extracted with EtOAc (3×150 ml), and the extract was washed with brine (100 ml), dried over Na 2 SO 4 and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (600 mg) as an off-white solid.

MS (ESI+): [M+H]+ 286.8.

B) 2-(Difluoromethyl)-6-iodo-3-methylimidazo[1,2-a]pyridine

To a stirred solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carbaldehyde (600 mg) in DCM (2 ml) was added DAST (845 mg) at −78° C. The reaction mixture then slowly warm up to room temperature, and stirred at the same temperature for 16 h. The reaction mixture was then diluted with DCM (100 ml) and washed with saturated NaHCO 3 solution (100 ml). The DCM layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (110 mg) as an off-white solid.

MS (ESI+): [M+H]+ 309.0.

C) 1-(2-(Difluoromethyl)-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-(trifluoromethyl)benzyl)oxy)pyridin-2(1H)-one and 2-(difluoromethyl)-6-iodo-3-methylimidazo[1,2-a]pyridine.

MS (ESI+): [M+H]+ 400.0.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one and (5-fluoro-pyridin-2-yl)-methanol.

MS (ESI+): [M+H]+ 391.0.

4-((4-Chlorobenzyl)oxy)-1-(2-((2,2-dimethylpropoxy)methyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) (2,2-Dimethylpropoxy)acetic acid

NaH (40% oil dispersion, 432 mg) was added to a solution of 2,2-dimethylpropan-1-ol (0.319 ml) in THF (15 ml) at 0° C. After stirring for 5 min, 2-bromoacetic acid (500 mg) was added. The mixture was refluxed under Ar atmosphere for 2 h. The mixture was quenched with water, washed with EtOAc, acidified with 1 M HCl (11 ml) and extracted with EtOAc. The organic layer was separated, dried over MgSO 4 and concentrated in vacuo to give the title compound (490 mg) as a pale pink oil.

1 H NMR (300 MHz, CDCl 3 ): δ 0.95 (9H, s), 3.24 (2H, s), 4.12 (2H, s).

B) 4-((4-Chlorobenzyl)oxy)-1-(2-((2,2-dimethylpropoxy)methyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one and (2,2-dimethylpropoxy)acetic acid.

MS (ESI+): [M+H]+ 466.1.

4-((4-Chlorobenzyl)oxy)-1-(2-((3,3-dimethylbutoxy)methyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) (3,3-Dimethylbutoxy)acetic acid

The title compound was obtained in an analogous manner to step A in example 100 using 3,3-dimethylbutan-1-ol and 2-bromoacetic acid.

1 H NMR (300 MHz, CDCl 3 ): δ 0.93 (9H, s), 1.58 (2H, t, J=7.4 Hz), 3.62 (2H, t, J=7.6 Hz), 4.10 (2H, s).

B) 4-((4-Chlorobenzyl)oxy)-1-(2-((3,3-dimethylbutoxy)methyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one and (3,3-dimethylbutoxy)acetic acid.

MS (ESI+): [M+H]+ 480.1.

4-((4-Chlorobenzyl)oxy)-1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

HATU (321 mg) was added to a solution of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (250 mg), N,N-diisopropylethylamine (0.367 ml) and propionic acid (57.3 mg) in DMF (3 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with brine and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO 4 , and concentrated in vacuo. The resulting residue in AcOH (1 ml) was stirred at 80° C. for 1 h. After evaporation of the solvent, the residue was purified by NH silica gel column chromatography (hexane/EtOAc to MeOH/EtOAc). The resulting solid was recrystallized twice from EtOH followed by THF to give the title compound (114 mg) as a white solid.

MS (ESI+): [M+H]+ 394.1.

1 H NMR (300 MHz, CDCl 3 ): δ 1.46 (3H, t, J=7.5 Hz), 2.93 (2H, q, J=7.5 Hz), 3.73 (3H, s), 5.03 (2H, s), 5.98-6.13 (2H, m), 7.12 (1H, dd, J=2.1, 8.5 Hz), 7.29-7.45 (6H, m), 7.77 (1H, d, J=8.7 Hz).

4-((4-Chlorobenzyl)oxy)-1-(1-methyl-2-propyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

HATU (321 mg) was added to a solution of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (250 mg), N,N-diisopropylethylamine (0.367 ml) and butyric acid (68.1 mg) in DMF (3 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with brine and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO 4 , and concentrated in vacuo. The resulting residue in AcOH (1 ml) was stirred at 80° C. for 1 h. After evaporation of the solvent, the residue was purified by NH silica gel column chromatography (hexane/EtOAc to MeOH/EtOAc). The resulting solid was recrystallized twice from EtOH followed by THF to give the title compound (126 mg) as a white solid.

MS (ESI+): [M+H]+ 408.1.

1 H NMR (300 MHz, CDCl 3 ): δ 1.07 (3H, t, J=7.5 Hz), 1.90 (2H, sxt, J=7.5 Hz), 2.81-2.95 (2H, m), 3.73 (3H, s), 5.03 (2H, s), 6.00-6.13 (2H, m), 7.12 (1H, dd, J=1.9, 8.3 Hz), 7.28-7.43 (6H, m), 7.76 (1H, d, J=8.3 Hz).

1-(2-Acetyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one

A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (596 mg), 1-(6-bromo-1-methyl-1H-benzimidazol-2-yl)ethanone (640 mg), N,N′-dimethylethylenediamine (0.272 ml), copper iodide (482 mg) and potassium carbonate (699 mg) in DMSO (10 ml) was stirred at 150° C. for 1 h. The mixture was quenched with NH 3 solution and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (16.8 mg) as a white solid.

MS (ESI+): [M+H]+ 408.1.

1 H NMR (300 MHz, CDCl 3 ): δ 2.85 (3H, s), 4.13 (3H, s), 5.03 (2H, s), 6.03-6.13 (2H, m), 7.27-7.43 (6H, m), 7.51 (1H, d, J=1.9 Hz), 7.97 (1H, d, J=8.7 Hz).

4-((4-Chlorobenzyl)oxy)-1-(2-(cyclopropylcarbonyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one and (6-bromo-1-methyl-1H-benzimidazol-2-yl)(cyclopropyl)methanone.

MS (ESI+): [M+H]+ 434.0.

1-(2-(5-Cyclopropyl-1,2-oxazol-3-yl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 5-cyclopropyl-1,2-oxazole-3-carboxylic acid.

MS (ESI+): [M+H]+ 457.2.

4-((4-Chlorobenzyl)oxy)-1-(1,2-dimethyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

HATU (321 mg) was added to a solution of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (250 mg), N,N-diisopropylethylamine (0.367 ml) and AcOH (0.044 ml) in DMF (3 ml) at room temperature. The mixture was stirred at room temperature for 2 h. Water (6 ml) was added to the mixture. The precipiate was collected by filtration and dissolved to AcOH (3 ml). The mixture was stirred at 80° C. for 1 h. After evaporation of the solvent, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (140 mg) as a pale pink solid.

MS (ESI+): [M+H]+ 380.0.

1 H NMR (300 MHz, CDCl 3 ): δ 2.63 (3H, s), 3.73 (3H, s), 5.03 (2H, s), 5.99-6.13 (2H, m), 7.12 (1H, dd, J=2.1, 8.5 Hz), 7.29-7.46 (6H, m), 7.73 (1H, d, J=8.3 Hz).

4-((4-Chlorobenzyl)oxy)-1-(1-methyl-2-(oxetan-3-yl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one and 3-oxetanecarboxylic acid.

MS (ESI+): [M+H]+ 422.1.

4-((4-Chlorobenzyl)oxy)-1-(2-cyclobutyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (90 mg), HATU (101 mg), N,N-diisopropylethylamine (0.130 ml), cyclobutanecarboxylic acid (0.024 ml) and DMF (2 ml) was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was dissolved in AcOH (2 ml), and the mixture was stirred at 90° C. for 1 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (22.72 mg) as an off-white solid.

MS (ESI+): [M+H]+ 420.2.

1 H NMR (300 MHz, DMSO-d 6 ): δ 1.87-2.19 (2H, m), 2.35-2.46 (4H, m), 3.66 (3H, s), 3.78-3.97 (1H, m), 5.16 (2H, s), 5.97 (1H, d, J=2.6 Hz), 6.09 (1H, s), 7.07 (1H, dd, J=1.9, 8.3 Hz), 7.44-7.54 (5H, m), 7.60 (2H, dd, J=7.9, 10.2 Hz).

4-((4-Chlorobenzyl)oxy)-1-(2-(2-fluoropropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) 4-((4-Chlorobenzyl)oxy)-1-(2-(2-hydroxypropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one and 3-hydroxybutanoic acid.

MS (ESI+): [M+H]+ 424.2.

B) 4-((4-Chlorobenzyl)oxy)-1-(2-(2-fluoropropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step B in example 52 using 4-((4-chlorobenzyl)oxy)-1-(2-(2-hydroxypropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one.

MS (ESI+): [M+H]+ 426.2.

4-((4-Fluorobenzyl)oxy)-1-(2-(3-methoxycyclobutyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) 6-Bromo-2-(3-methoxycyclobutyl)-1-methyl-1H-benzimidazole

The title compound was obtained as a diastereomeric mixture in an analogous manner to step A in example 8 using 4-bromo-N 2 -methylbenzene-1,2-diamine and 3-methoxycyclobutanecarboxylic acid.

MS (ESI+): [M+H]+ 294.8.

B) 4-((4-Fluorobenzyl)oxy)-1-(2-(3-methoxycyclobutyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained as a diastereomeric mixture in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 6-bromo-2-(3-methoxycyclobutyl)-1-methyl-1H-benzimidazole.

MS (ESI+): [M+H]+ 434.2.

4-((5-Chloropyridin-2-yl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (200 mg), (5-chloropyridin-2-yl)-methanol (152 mg) and tributylphosphine (437 mg) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (536 mg). The mixture was stirred under sonication at 50° C. for 3 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM (100 ml), washed with water and brine (30 ml), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) followed by preparative HPLC to give the title compound (40 mg) as a white solid.

MS (ESI+): [M+H]+ 407.4.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.04-1.09 (4H, m), 2.26-2.32 (1H, m), 3.84 (3H, s), 5.23 (2H, s), 5.96 (1H, s), 6.12 (1H, dd, J=2.6, 7.7 Hz), 7.04 (1H, m), 7.50-7.52 (2H, m), 7.59-7.61 (2H, m), 8.02-8.04 (1H, m), 8.67 (1H, s).

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(3-oxocyclobutyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) N-(4-Bromo-2-(methylamino)phenyl)-3-oxocyclobutanecarboxamide

To a stirred solution of 3-oxocyclobutanecarboxylic acid (1.1 g) in DMF (50 ml) were added HATU (5.7 g) and N,N-diisopropylethylamine (4.2 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 30 min. A solution of 4-bromo-N 2 -methylbenzene-1,2-diamine (2.0 g) in DMF (2 ml) was added, and the resultant mixture was stirred at the same temperature for 18 h. The mixture was then concentrated in vacuo, and the residue was diluted with DCM (200 ml) and washed with saturated NH 4 Cl (100 ml), saturated NaHCO 3 (60 ml), water (100 ml) and brine (100 ml). The DCM layer was then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (2.7 g) as an off-white solid.

MS (ESI+): [M+H]+ 297.2.

B) 3-(6-Bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutanone

To a stirred solution of N-(4-bromo-2-(methylamino)phenyl)-3-oxocyclobutanecarboxamide (2.7 g) in CH 3 CN (20 ml) was added glacial AcOH (2 ml) at room temperature, and then mixture was heated at reflux for 3 h. The mixture was then cooled to room temperature, concentrated in vacuo, and poured into ice-cold saturated NaHCO 3 (100 ml). The mixture was extracted with EtOAc, and the extract was washed with water (100 ml) and brine (100 ml), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (2.0 g) as an off-white solid.

MS (ESI+): [M+H]+ 281.2.

C) 4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(3-oxocyclobutyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 3-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutanone.

MS (ESI+): [M+H]+ 418.0.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)methoxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one and (5-(trifluoromethyl)pyridin-2-yl)methanol.

MS (ESI+): [M+H]+ 441.2.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((3,4-difluorobenzyl)oxy)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (3,4-difluorophenyl)methanol (153 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM (60 ml), washed with water and brine (30 ml), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (85 mg) as a white solid.

MS (ESI+): [M+H]+ 408.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.02-1.11 (4H, m), 2.24-2.29 (1H, m), 3.85 (3H, s), 5.14 (2H, s), 5.97 (1H, d, J=2.6 Hz), 6.10 (1H, dd, J=2.7, 7.7 Hz), 7.04 (1H, dd, J=1.8, 8.4 Hz), 7.31-7.37 (1H, m), 7.46-7.60 (5H, m).

4-((4-Fluorobenzyl)oxy)-1-(2-(3-hydroxycyclobutyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a stirred solution of 4-((4-fluorobenzyl)oxy)-1-(1-methyl-2-(3-oxocyclobutyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one (80 mg) in a mixture of THF (10 ml) and MeOH (3 ml) was added NaBH 4 (15 mg) at 0° C. The mixture was then allowed to warm to room temperature, and stirred for 3 h. The reaction mixture was then quenched with saturated NH 4 Cl (5 ml), and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (50 mg) as an off-white solid.

MS (ESI+): [M+H]+ 420.4.

1-(2-Cyclopropyl-3-(hydroxymethyl)imidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A) 2-Cyclopropyl-6-iodoimidazo[1,2-a]pyridine

A mixture of 2-bromo-1-cyclopropylethanone (18.0 g), 5-iodopyridin-2-amine (5.2 g) and EtOH (100 ml) was heated at reflux for 16 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The resulting residue was diluted with DCM (200 ml), and washed with water (100 ml) and brine (100 ml). The DCM layer was dried over Na 2 SO 4 and concentrated in vacuo. The crude product thus obtained was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.53 g) as a yellow solid.

MS (ESI+): [M+H]+ 285.0.

B) (2-Cyclopropyl-6-iodoimidazo[1,2-a]pyridin-3-yl)methanol

To a solution of 2-cyclopropyl-6-iodoimidazo[1,2-a]pyridine (1.5 g) in AcOH (20 ml) were added sodium acetate (2.39 g) and 40% aqueous formaldehyde solution (4 ml), and the mixture was heated at 50° C. for 6 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo.

The resulting residue was diluted with DCM (200 ml), and the DCM layer was washed successively with saturated NaHCO 3 (100 ml), water (100 ml) and brine (100 ml). The DCM layer was dried over Na 2 SO 4 and concentrated in vacuo. The crude product thus obtained was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (600 mg) as a yellow solid.

MS (ESI+): [M+H]+ 315.2.

C) 1-(2-Cyclopropyl-3-(hydroxymethyl)imidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and (2-cyclopropyl-6-iodoimidazo[1,2-a]pyridin-3-yl)methanol.

MS (ESI+): [M+H]+ 406.0.

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-(pyridin-3-ylmethoxy)pyridin-2(1H)-one

A) 1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one

To a stirred solution of 4-(benzyloxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (127 mg) in MeOH (8 ml) was added Pd/C (10%, 25 mg), and the mixture was stirred under H 2 atmosphere at room temperature for 4 h. The solid was then filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (56 mg) as an off-white solid.

MS (ESI+): [M+H]+ 282.2.

B) 1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-(pyridin-3-ylmethoxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one and pyridin-3-ylmethanol.

MS (ESI+): [M+H]+ 373.4.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((3,5-difluorobenzyl)oxy)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (3,5-difluorophenyl)methanol (153 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (56 mg) as an off-white solid.

MS (ESI+): [M+H]+ 408.6.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.04-1.09 (4H, m), 2.26 (1H, m), 3.85 (3H, s), 5.19 (2H, s), 5.95 (1H, d, J=2.6 Hz), 6.13 (1H, dd, J=2.6, 7.6 Hz), 7.04 (1H, dd, J=1.7, 8.5 Hz), 7.21-7.25 (3H, m), 7.50-7.52 (2H, m), 7.60 (1H, d, J=7.6 Hz).

4-(((1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-2-oxo-1,2-dihydropyridin-4-yl)oxy)methyl)benzonitrile

The title compound was obtained in an analogous manner to example 75 using 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one and 4-(hydroxymethyl)benzonitrile

MS (ESI+): [M+H]+ 397.2.

4-((5-Chloro-2-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chloro-2-thienyl)methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, and washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (72 mg) as a white solid.

MS (ESI+): [M+H]+ 412.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.02-1.11 (4H, m), 2.23-2.28 (1H, m), 3.85 (3H, s), 5.29 (2H, s), 6.03-6.07 (2H, m), 7.02 (1H, dd, J=1.8, 8.5 Hz), 7.08 (1H, d, J=3.7 Hz), 7.16 (1H, d, J 3.8, Hz), 7.51 (2H, dd, J=3.5, 5.4 Hz), 7.57 (1H, d, J=7.4 Hz).

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-(pyridin-4-ylmethoxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one and pyridin-4-ylmethanol.

MS (ESI+): [M+H]+ 373.3.

1-(2-Cyclopropyl-3-(methoxymethyl)imidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

To a stirred suspension of NaH (40% oil dispersion, 22 mg) in THF (9 ml) was added a solution of 1-(2-cyclopropyl-3-(hydroxymethyl)imidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (100 mg) in THF (1 ml) at 0° C., and then the mixture was allowed to warm to room temperature and stirred for 30 min. Iodomethane (22 pa) in THF (0.5 ml) was added, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice-water and extracted with DCM. The combined DCM layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) followed by recrystallization from DCM/hexane to give the title compound (40 mg) as a white solid.

MS (ESI+): [M+H]+ 420.3.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(2-thienylmethoxy)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), 2-thienylmethanol (100 μL) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, and the DCM layer was washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (60 mg) as a white solid.

MS (ESI+): [M+H]+ 377.8.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.04-1.11 (4H, m), 2.24-2.28 (1H, m), 3.85 (3H, s), 5.34 (2H, s), 6.05-6.07 (2H, m), 7.03-7.08 (2H, m), 7.27 (1H, d, J=2.8 Hz), 7.50-7.52 (2H, m), 7.57 (1H, d, J=7.2 Hz), 7.61 (1H, d, J=4.9 Hz).

4-((4-Fluorobenzyl)oxy)-1-(3-methyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

A) 6-Iodo-3-methylimidazo[1,2-a]pyridine-2-carbohydrazide

To a stirred solution of ethyl 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylate (250 mg) in EtOH (5 ml) was added hydrazine hydrate (0.14 ml) at room temperature. The reaction vessel was sealed and heated at 80° C. for 16 h. The mixture was then cooled to room temperature, and the reaction mixture was concentrated in vacuo. The residue was washed with EtOAc to give the title compound (200 mg) as a light yellow solid.

MS (ESI+): [M+H]+ 317.0.

B) 6-Iodo-3-methyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridine

To a stirred solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carbohydrazide (200 mg) in AcOH (0.5 ml) was added triethyl orthoacetate (2 ml) at room temperature, and the reaction mixture was heated at reflux for 4 h. The mixture was then cooled to room temperature, and the reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc, and the EtOAc layer was washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (100 mg) as a light yellow solid.

MS (ESI+): [M+H]+ 340.8.

C) 4-((4-Fluorobenzyl)oxy)-1-(3-methyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 5 using 6-iodo-3-methyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridine and 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one.

MS (ESI+): [M+H]+ 432.2.

4-(Benzyloxy)-1-(1-methyl-2-propyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) 6-Bromo-1-methyl-2-propyl-1H-benzimidazole

To a stirred mixture of butyric acid (986 mg) and 4-bromo-N 2 -methylbenzene-1,2-diamine (1.5 g) was added POCl 3 (10 ml), and the mixture was heated at reflux for 1 h. The mixture was then cooled to room temperature, and concentrated in vacuo. The residue was poured into ice-cold saturated NaHCO 3 . The mixture was extracted with EtOAc, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product thus obtained was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.4 g) as an off-white solid.

MS (ESI+): [M+H]+ 252.8.

B) 4-(Benzyloxy)-1-(1-methyl-2-propyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a stirred degassed mixture of 6-bromo-1-methyl-2-propyl-1H-benzimidazole (680 mg), 4-(benzyloxy)pyridin-2(1H)-one (450 mg), potassium carbonate (927 mg) and dioxane (15 ml) were added copper iodide (170 mg) and trans-N,N′-dimethylcyclohexane-1,2-diamine (128 mg). The reaction vessel was sealed and heated at 110° C. for 16 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (320 mg) as an off-white solid.

MS (ESI+): [M+H]+ 374.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.99 (3H, t, J=7.4 Hz), 1.78-1.83 (2H, m), 2.86 (2H, t, =7.5 Hz), 3.74 (3H, s), 5.15 (2H, s), 5.98 (1H, d, J=2.6 Hz), 6.09 (1H, dd, J=2.6, 7.5 Hz), 7.06 (1H, dd, J=1.9, 8.4 Hz), 7.37-7.48 (5H, m), 7.53 (1H, d, J=1.7 Hz), 7.58 (2H, d, J=7.8 Hz).

4-((3-Chlorobenzyl)oxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) 4-((3-Chlorobenzyl)oxy)pyridine 1-oxide

To an ice-cold suspension of NaH (40% oil dispersion, 1.51 g) in THF (60 ml) was added (3-chlorophenyl)methanol (3.0 g) at 0° C. The reaction mixture was stirred at the same temperature for 30 min followed by the portionwise addition of 4-chloropyridine 1-oxide (2.73 g) at 0° C. The resulting reaction mixture was stirred for 1 h at 0° C. and then warmed to room temperature. After 2 h, the reaction mixture was poured into ice-water (100 g) and extracted with DCM. The DCM layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was triturated with Et 2 O to give the title compound (2.2 g) as a brown solid.

MS (ESI+): [M+H]+ 236.0.

B) 4-((3-Chlorobenzyl)oxy)pyridin-2(1H)-one

To 4-((3-chlorobenzyl)oxy)pyridine 1-oxide (2.0 g) was added acetic anhydride (20 ml), and the solution was heated at reflux for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with MeOH/NaOH (1:1, 150 ml) and heated at reflux for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted with DCM. The combined DCM layer was concentrated in vacuo and the crude residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (984 mg) as an off-white solid.

MS (ESI+): [M+H]+ 236.0.

C) 4-((3-Chlorobenzyl)oxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a stirred degassed mixture of 6-bromo-2-cyclopropyl-1-methyl-1H-benzimidazole (694 mg), 4-((3-chlorobenzyl)oxy)pyridin-2(1H)-one (500 mg) and potassium carbonate (588 mg) in dioxane (30 ml) were added copper iodide (80 mg) and trans-N,N′-dimethylcyclohexane-1,2-diamine (60 mg). The reaction vessel was sealed and heated at 110° C. for 16 h. The reaction mixture was then cooled to room temperature, and the volatile matters were removed in vacuo. The residue was diluted with DCM, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) followed by recrystallization from dioxane/water to give the title compound (252 mg) as a white solid.

MS (ESI+): [M+H]+ 405.8.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.02-1.11 (4H, m), 2.25-2.29 (1H, m), 3.85 (3H, s), 5.18 (2H, s), 5.97 (1H, d, J=2.4 Hz), 6.12 (1H, dd, J=2.5, 8.5 Hz), 7.04 (1H, dd, J=1.6, 8.5 Hz), 7.43-7.48 (3H, m), 7.49-7.55 (3H, m), 7.59 (1H, d, J=7.6 Hz).

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-(pyrimidin-5-ylmethoxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one and pyrimidin-5-ylmethanol.

MS (ESI+): [M+H]+ 374.2.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((2-methyl-1,3-thiazol-5-yl)methoxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one and (2-methyl-1,3-thiazol-5-yl)methanol.

MS (ESI+): [M+H]+ 393.0.

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((3-fluorobenzyl)oxy)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (3-fluorophenyl)-methanol (134 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM (100 ml), and the DCM layer was washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (45 mg) as a white solid.

MS (ESI+): [M+H]+ 389.8.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.88-0.94 (4H, m), 2.04-2.10 (1H, m), 2.47 (3H, m), 5.19 (2H, s), 5.99 (1H, d, J=2.7 Hz), 6.16 (1H, dd, J=2.8, 7.7 Hz), 7.11 (1H, dd, J=1.9, 9.5 Hz), 7.19-7.23 (1H, m), 7.31 (2H, d, J=7.4 Hz), 7.42-7.51 (2H, m), 7.66 (1H, d, J=7.6 Hz), 8.37 (1H, d, J=1.4 Hz).

4-((4-Chloro-3-fluorobenzyl)oxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (4-chloro-3-fluorophenyl)methanol (114 mg) and tributylphosphine (258 μl) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (265 mg). The mixture was stirred under sonication at 60° C. for 2 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (25 mg) as an off-white solid.

MS (ESI+): [M+H]+ 397.2.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.03-1.09 (4H, m), 2.25-2.28 (1H, m), 3.85 (3H, s), 5.18 (2H, s), 5.96 (1H, d, J=2.6 Hz), 6.11 (1H, dd, J=2.6, 7.6 Hz), 7.04 (1H, dd, J=1.8, 8.4 Hz), 7.35 (1H, d, J=9.4 Hz), 7.51-7.55 (3H, m), 7.59 (1H, d, J 7.6 Hz), 7.66 (1H, t, J=8.0 Hz).

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-(2-thienylmethoxy)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), 2-thienylmethanol (121 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (45 mg) as an off-white solid.

MS (ESI+): [M+H]+ 378.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.88-0.92 (4H, m), 2.06-2.08 (1H, m), 2.47 (3H, s), 5.35 (2H, s), 6.07-6.12 (2H, m), 7.07 (1H, dd, J=3.5, 4.9 Hz), 7.09-7.13 (1H, m), 7.27 (1H, d, J=3.1 Hz), 7.43 (1H, d, J=9.4 Hz), 7.61 (1H, d, J=5.0 Hz), 7.64 (1H, d, J=7.5 Hz), 8.37 (1H, s).

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-thienylmethoxy)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), 3-thienylmethanol (121 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (80 mg) as a white solid.

MS (ESI+): [M+H]+ 378.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.88-0.94 (4H, m), 2.04-2.10 (1H, m), 2.47 (3H, s), 5.15 (2H, s), 6.02 (1H, d, J=2.6 Hz), 6.10 (1H, dd, J=2.6, 7.6 Hz), 7.07 (1H, dd, J=1.8, 9.5 Hz), 7.19 (1H, d, J=4.9 Hz), 7.43 (1H, d, J=9.4 Hz), 7.59 (1H, dd, J=2.9, 4.8 Hz), 7.64-7.66 (2H, m), 8.37 (1H, s).

4-((4-Fluorobenzyl)oxy)-1-(2-(3-hydroxy-3-methylcyclobutyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a stirred suspension of cerium chloride (532 mg) in THF (30 ml) was added methyllithium (3 M in diethoxymethane, 719 μl) at −78° C. A cold solution of 4-((4-fluorobenzyl)oxy)-1-(1-methyl-2-(3-oxocyclobutyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one (150 mg) in dry THF (3 ml) was slowly added to the reaction mixture at −78° C. and stirred for 1 h at the same temperature. The reaction mixture was quenched with saturated NH 4 Cl at −78° C. and then warmed up to room temperature. The mixture was extracted with DCM, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) followed by purification by preparative HPLC to give the title compound (33 mg) as a white solid.

MS (ESI+): [M+H]+ 434.3.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(furan-2-ylmethoxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one and furan-2-ylmethanol.

MS (ESI+): [M+H]+ 361.8.

4-((4-Chlorobenzyl)oxy)-1-(2-((1RS,2RS)-2-fluorocyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (200 mg), HATU (224 mg), cis-2-fluoro-cyclopropanecarboxylic acid (100 mg), N,N-diisopropylethylamine (288 μl) and DMF (4 ml) was stirred at room temperature under a dry atmosphere (CaCl 2 tube) for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was dissolved in AcOH (4.0 ml) and stirred at 90° C. for 1 h. After AcOH was evaporated, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (37.6 mg) as an off-white solid.

MS (ESI+): [M+H]+ 424.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.32-1.48 (1H, m), 1.85-2.01 (1H, m), 3.85 (3H, s), 5.00-5.25 (3H, m), 5.98 (1H, d, J=2.8 Hz), 6.11 (1H, dd, J=2.8, 7.7 Hz), 7.09 (1H, dd, J=1.9, 8.4 Hz), 7.50 (4H, s), 7.56 (1H, d, J=1.8 Hz), 7.61 (2H, d, J 8.0 Hz). 1H was overlapped with DMSO peak, and not detected.

4-((4-Chlorobenzyl)oxy)-1-(2-((1RS,2SR)-2-fluorocyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (200 mg), HATU (224 mg), trans-2-fluoro-cyclopropanecarboxylic acid (100 mg), N,N-diisopropylethylamine (288 μl) and DMF (4 ml) was stirred at room temperature under a dry atmosphere (CaCl 2 tube) for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was dissolved in AcOH (4.0 ml) and stirred at 90° C. for 1 h. After AcOH was evaporated, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (25.8 mg) as a pale yellow solid.

MS (ESI+): [M+H]+424.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.39-1.50 (1H, m), 1.64-1.82 (1H, m), 2.85-3.00 (1H, m), 3.88 (3H, s), 4.96-5.20 (3H, m), 5.97 (1H, d, J=2.8 Hz), 6.10 (1H, dd, J=2.7, 7.6 Hz), 7.07 (1H, dd, J=2.0, 8.4 Hz), 7.50 (4H, s), 7.52-7.56 (2H, m), 7.58 (1H, d, J=7.5 Hz).

Methyl(1RS,2SR)-2-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate

Iodomethane (0.111 ml) was added to a solution of (1RS,2SR)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylic acid (400 mg) and potassium carbonate (246 mg) in DMF (5 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (MeOH/EtOAc) to give the title compound (205 mg) as a pink solid.

MS (ESI+): [M+H]+ 464.1.

4-((5-Chloro-2-thienyl)methoxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chloro-2-thienyl)methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (7 mg) as a white solid.

MS (ESI+): [M+H]+ 412.4.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.88-0.91 (4H, m), 2.05-2.08 (1H, m), 2.47 (3H, s), 5.30 (2H, s), 6.06 (1H, d, J=2.5 Hz), 6.09 (1H, dd, J=2.5, 7.5 Hz), 7.08-7.12 (2H, m), 7.17 (1H, d, J=3.7 Hz), 7.43 (1H, d, J=9.4 Hz), 7.65 (1H, d, J=7.6 Hz), 8.36 (1H, s).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-methoxypyridin-2-yl)methoxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using (5-methoxypyridin-2-yl)methanol and 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one.

MS (ESI+): [M+H]+ 403.0.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-methylpyridin-2-yl)methoxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using (5-methylpyridin-2-yl)methanol and 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one.

MS (ESI+): [M+H]+ 387.2.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-methylbenzyl)oxy)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (170 mg), (4-methylphenyl)methanol (148 mg) and tributylphosphine (454 μl) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (458 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (50 mg) as an off-white solid.

MS (ESI+): [M+H]+ 386.2.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.02-1.09 (4H, m), 2.24-2.28 (1H, m), 2.32 (3H, s), 3.84 (3H, s), 5.09 (2H, s), 5.95 (1H, d, J=2.5 Hz), 6.07 (1H, dd, J=2.7, 7.6 Hz), 7.03 (1H, dd, J=1.8, 8.5 Hz), 7.23 (2H, d, J=7.9 Hz), 7.35 (2H, d, J=7.8 Hz), 7.50-7.52 (2H, m), 7.56 (1H, d, J=7.6 Hz).

4-((5-Chloro-3-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chloro-3-thienyl)methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) followed by preparative HPLC to give the title compound (20 mg) as a white solid.

MS (ESI+): [M+H]+ 412.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.02-1.11 (4H, m), 2.24-2.32 (1H, m), 3.85 (3H, s), 5.05 (2H, s), 5.98 (1H, d, J=2.6 Hz), 6.06 (1H, dd, J=2.7, 7.6 Hz), 7.03 (1H, dd, J=1.8, 8.5 Hz), 7.20 (1H, d, J=1.5 Hz), 7.51 (2H, dd, J=3.5, 5.4 Hz), 7.56-7.58 (2H, m).

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(1,2-oxazol-5-yl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 1,2-oxazole-5-carboxylic acid.

MS (ESI+): [M+H]+ 417.1

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(5-methyl-1,3-oxazol-4-yl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 5-methyl-1,3-oxazole-4-carboxylic acid.

MS (ESI+): [M+H]+ 431.1.

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((3,4-difluorobenzyl)oxy)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (3,4-difluorophenyl)methanol (153 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (40 mg) as a white solid.

MS (ESI+): [M+H]+ 408.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.88-0.92 (4H, m), 2.06-2.08 (1H, m), 5.14 (2H, s), 6.00 (1H, d, J=2.4 Hz), 6.15 (1H, dd, J=2.5, 7.6 Hz), 7.11 (1H, d, J=9.4 Hz), 7.34 (1H, m), 7.43 (1H, d, J=9.4 Hz), 7.48-7.51 (1H, m), 7.55-7.60 (1H, m), 7.66 (1H, d, J=7.64 Hz), 8.37 (1H, s). 3H was overlapped with DMSO peak, and not detected.

4-((4-Chlorobenzyl)oxy)-1-(2-ethyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

A) 2-Bromopentan-3-one

To a stirred solution of pentan-3-one (5.0 g) in Et 2 O (50 ml) was added a solution of bromine (2.5 ml) in Et 2 O (50 ml) over a period of 2 h at 0° C., and then the mixture was stirred at room temperature for 4 h. The reaction mixture was then quenched with aqueous sodium thiosulfate (0.1 M, 100 ml) at 0° C. The reaction mixture was then extracted with ether, washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo to give the title compound (6.0 g) as a brown liquid.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.98 (3H, t, J=6.3 Hz), 1.63 (3H, d, J=6.6 Hz), 2.56-2.66 (1H, m), 2.74-2.83 (1H, m), 4.79 (1H, q, J=6.8 Hz).

B) 2-Ethyl-6-iodo-3-methylimidazo[1,2-a]pyridine

To a stirred mixture of 2-bromopentan-3-one (2.0 g), 2-amino-5-iodopyridine (1.0 g) and EtOH (50 ml) was heated at reflux for 16 h. The reaction mixture was cooled and concentrated in vacuo. The residue was diluted with water (100 ml), and extracted with DCM. The DCM layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (400 mg) as a yellow solid.

MS (ESI+): [M+H]+ 286.8.

C) 4-((4-Chlorobenzyl)oxy)-1-(2-ethyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a stirred degassed mixture of 2-ethyl-6-iodo-3-methylimidazo[1,2-a]pyridine (400 mg), 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (263 mg), potassium carbonate (462 mg) and dioxane (5 ml) were added copper iodide (42 mg) and trans-N,N′-dimethylcyclohexane-1,2-diamine (31 mg). The reaction vessel was sealed and heated at 110° C. for 16 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM, and the DCM layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (110 mg) as an off-white solid.

MS (ESI+): [M+H]+ 394.0.

(1RS,2SR)-2-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarbonitrile

A) (1RS,2SR)-2-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylic acid

A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (2.0 g), 3-oxabicyclo[3.1.0]hexane-2,4-dione (0.662 g) and triethylamine (1.175 ml) in THF (80 ml) was stirred at room temperature overnight. After concentration of the mixture in vacuo, AcOH (80 ml) was added to the residue. The mixture was stirred at 80° C. for 1 h. After concentration of the mixture in vacuo, the mixture was neutralized with saturated NaHCO 3 solution at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The resulting solid was washed with IPE and dried to give the title compound (1.67 g) as a brown solid.

MS (ESI+): [M+H]+ 450.1.

B) (1RS,2SR)-2-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxamide

To a solution of (1RS,2SR)-2-(6-(4-((4-chlorobenzylμ)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylic acid (500 mg, 1.11 mmol) and triethylamine (0.465 ml, 3.33 mmol) in THF (10 ml) was added ethyl carbonochloridate (0.319 ml, 3.33 mmol) dropwise at 0° C. Stirring was continued at 0° C. for 1.5 h and then 28% NH 3 solution (0.34 ml, 5.57 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The resulting solid was washed with IPE to give the title compound (195 mg) as a white solid.

MS (ESI+): [M+H]+ 449.1.

C) (1RS,2SR)-2-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarbonitrile

Trifluoroacetic anhydride (0.181 ml) was added to a solution of (1RS,2SR)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxamide (195 mg) and pyridine (0.105 ml) in THF (5 ml) at 0° C. The mixture was stirred at 0° C. for 2 h. The mixture was quenched with saturated NaHCO 3 solution at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/EtOAc). The residue was recrystallized from EtOH/hexane to give the title compound (35 mg) as a white solid.

MS (ESI+): [M+H]+ 431.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.62-1.77 (1H, m), 1.96-2.07 (1H, m), 2.37-2.46 (1H, m), 2.91-3.05 (1H, m), 3.90 (3H, s), 5.16 (2H, s), 5.99 (1H, d, J=2.3 Hz), 6.11 (1H, dd, J=2.5, 7.8 Hz), 7.12 (1H, d, J=8.3 Hz), 7.50 (4H, s), 7.60-7.68 (3H, m).

4-((4-Chlorobenzyl)oxy)-1-(2-((1RS,2SR)-2-(hydroxymethyl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A suspension of methyl(1RS,2SR)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate (200 mg) in THF (1.5 ml) and MeOH (0.750 ml) was added dropwise to a solution of NaBH 4 (32.6 mg) and CaCl 2 (71.8 mg) in THF (3 ml) and MeOH (2 ml) at 0° C. The mixture was stirred at room temperature under Ar atmosphere overnight. NaBH 4 (300 mg) was added to the m resulting mixture at 50° C., and the mixture was stirred at 50° C. overnight. The mixture was neutralized with 1 M HCl at 0° C. and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO 3 solution and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (156 mg) as a white solid.

MS (ESI+): [M+H]+ 436.1.

1 H NMR (400 MHz, CDCl 3 ): δ 0.88-0.95 (1H, m), 1.30-1.37 (1H, m), 1.79-1.90 (1H, m), 2.07-2.15 (1H, m), 3.30 (1H, t, J=10.8 Hz), 3.84 (3H, s), 4.05-4.16 (1H, m), 5.03 (2H, s), 5.52 (1H, brs), 6.03-6.09 (2H, m), 7.13 (1H, dd, J=1.9, 8.4 Hz), 7.29-7.33 (1H, m), 7.34-7.42 (5H, m), 7.70 (1H, d, J=8.5 Hz).

Methyl(1RS,2SR)-2-(6-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate

A) 4-(Benzyloxy)-1-(3-(methylamino)-4-nitrophenyl)pyridin-2(1H)-one

The mixture of 4-(benzyloxy)pyridin-2(1H)-one (5.0 g), 5-bromo-N-methyl-2-nitroaniline (5.74 g), copper iodide (4.73 g), N,N′-dimethylethylenediamine (2.8 ml) and potassium carbonate (10.30 g) in DMSO (250 ml) was stirred at 150° C. under N 2 for 1 h. After cooling to room temperature, 28% NH 3 solution was added to the resulting mixture. The resulting suspension was filtered. The precipitate was washed with water and IPA and dried to give the title compound (5.1 g) as a yellow solid.

MS (ESI+): [M+H]+ 352.1.

B) 1-(4-Amino-3-(methylamino)phenyl)-4-(benzyloxy)pyridin-2(1H)-one

Zinc (9.49 g) was added to a solution of 4-(benzyloxy)-1-(3-(methylamino)-4-nitrophenyl)pyridin-2(1H)-one (5.1 g) in AcOH (120 ml) at room temperature. The mixture was stirred at room temperature for 2 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The mixture was neutralized with saturated NaHCO 3 solution at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was washed with IPE and dried to give the title compound (3.5 g) as a brown solid.

MS (ESI+): [M+H]+ 322.1.

C) Methyl(1RS,2SR)-2-(6-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate

HATU (4.97, g) was added to a solution of 1-(4-amino-3-(methylamino)phenyl)-4-(benzyloxy)pyridin-2(1H)-one (3.5 g), (1RS,2SR)-2-(methoxycarbonyl)cyclopropanecarboxylic acid (1.884 g) and N,N-diisopropylethylamine (3.80 ml) in DMF (70 ml) at room temperature. The mixture was stirred at room temperature for 1 h. To the resulting mixture was added water, and the resulting precipitate was collected by filtration and washed with water and IPA. The obtained solid was dissolved in AcOH (35 ml). The mixture was stirred at 80° C. for 1 h. After evaporation of the mixture, the residue was diluted with saturated NaHCO 3 solution and EtOAc. The organic layer was washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was washed with IPE to give the title compound (2.9 g) as a pink solid.

MS (ESI+): [M+H]+ 430.1.

4-((4-Chloro-3-fluorobenzyl)oxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (4-chloro-3-fluorophenyl)methanol (170 mg) and tributylphosphine (322 mg) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg) in THF (5 ml). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM, and the DCM layer was washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (50 mg) as a white solid.

MS (ESI+): [M+H]+ 424.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.88-0.92 (4H, m), 2.04-2.08 (1H, m), 5.19 (2H, s), 5.99 (1H, d, J=2.5 Hz), 6.16 (1H, dd, J=2.6, 7.7 Hz), 7.11 (1H, dd, J=1.7, 9.4 Hz), 7.34 (1H, d, J=7.7 Hz), 7.43 (1H, d, J=9.5 Hz), 7.54 (1H, d, J=9.3 Hz), 7.64-7.68 (2H, m), 8.37 (1H, s). 3H was overlapped with DMSO peak, and not detected.

4-(Benzyloxy)-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

Methylmagnesium bromide (1 M in THF, 27.0 ml) was added to a solution of methyl(1RS,2SR)-2-(6-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate (2.9 g) in THF (130 ml) at 0° C. The mixture was stirred at room temperature under N 2 atmosphere for 3 h. The mixture was quenched with saturated NH 4 Cl solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (MeOH/EtOAc). The resulting solid was recrystallized from EtOH/IPE to give the title compound (1.6 g) as a white solid.

MS (ESI+): [M+H]+ 430.4.

1 H NMR (400 MHz, CDCl 3 ): δ 1.28 (3H, s), 1.33-1.40 (4H, m), 1.52-1.70 (2H, m), 1.97-2.08 (1H, m), 3.82 (3H, s), 5.06 (2H, s), 6.02-6.13 (2H, m), 6.88 (1H, s), 7.11 (1H, d, J=8.8 Hz), 7.29 (1H, d, J=7.5 Hz), 7.34-7.46 (6H, m), 7.64 (1H, d, J=8.3 Hz).

4-((4-Chlorobenzyl)oxy)-1-(2-((1R*,2S*)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (optically active, AYH tR1)

(1RS,2SR)-4-((4-Chlorobenzyl)oxy)-1-(2-(2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (0.830 g) was resolved by a preparative SFC (CHIRALPAK AYH, CO 2 /EtOH/CH 3 CN=600/200/200) to give a white solid (355 mg, >99% ee). This solid was recrystallized from IPA to give the title compound (270 mg) as a white solid.

MS (ESI+): [M+H]+ 464.1.

1 H NMR (400 MHz, CDCl 3 ): δ 1.28 (3H, s), 1.32-1.42 (4H, m), 1.52-1.59 (1H, m), 1.61-1.68 (1H, m), 1.93-2.10 (1H, m), 3.82 (3H, s), 5.02 (2H, s), 6.00-6.12 (2H, m), 6.86 (1H, s), 7.11 (1H, dd, J=1.6, 8.4 Hz), 7.28-7.46 (6H, m), 7.64 (1H, d, J=8.4 Hz).

Analysis of enentiomeric excess

Column: CHIRALPAK AYH (2.0×150 mm)

Mobile phase: CO 2 /EtOH/CH 3 CN=600/200/200 (v/v/v)

Flow rate: 1.5 ml/min

Temperature: 35° C.

Detection: UV: 220 nm

Retention time: 1.52 min

4-((4-Chlorobenzyl)oxy)-1-(2-((1R*,2S*)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (optically active, AYH tR2)

(1RS,2SR)-4-((4-Chlorobenzyl)oxy)-1-(2-(2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (0.830 g) was resolved by a preparative SFC (CHIRALPAK AYH, CO 2 /EtOH/CH 3 CN=600/200/200) to give a white solid (351 mg, >99% ee). This solid was recrystallized from IPA to give the title compound (279 mg) as a white solid.

MS (ESI+): [M+H]+ 464.2.

1 H NMR (400 MHz, CDCl 3 ): δ 1.28 (3H, s), 1.33-1.40 (4H, m), 1.49-1.67 (2H, m), 1.95-2.06 (1H, m), 3.82 (3H, s), 5.02 (2H, s), 6.05 (2H, d, J=2.6 Hz), 6.86 (1H, s), 7.11 (1H, d, J=8.4 Hz), 7.28-7.32 (1H, m), 7.34-7.46 (5H, m), 7.64 (1H, d, J=8.4 Hz).

Analysis of enentiomeric excess

Column: CHIRALPAK AYH (2.0×150 mm)

Mobile phase: CO 2 /EtOH/CH 3 CN=600/200/200 (v/v/v)

Flow rate: 1.5 ml/min

Temperature: 35° C.

Detection: UV: 220 nm

Retention time: 2.88 min

4-(Benzyloxy)-1-(2-((1RS,2SR)-2-(2-fluoropropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

BAST (0.172 ml) was added to a solution of 4-(benzyloxy)-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg) in toluene (2 ml) at 0° C. The mixture was stirred at 0° C. under a dry atmosphere for 30 min. The mixture was quenched with saturated NaHCO 3 solution at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/EtOAc) to give the title compound (25 mg) as an off-white solid.

MS (ESI+): [M+H]+ 432.4.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.00 (3H, d, J=20.8 Hz), 1.13-1.34 (4H, m), 1.57-1.67 (1H, m), 1.67-1.81 (1H, m), 2.31-2.44 (1H, m), 3.83 (3H, s), 5.16 (2H, s), 5.99 (1H, d, J=2.3 Hz), 6.09 (1H, dd, J=2.4, 7.7 Hz), 7.07 (1H, d, J=8.5 Hz), 7.33-7.50 (5H, m), 7.54 (1H, s), 7.60 (2H, dd, J=8.0, 16.3 Hz).

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((5-fluorothiophen-2-yl)methoxy)pyridin-2(1H)-one

A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (285 mg), (5-fluorothiophen-2-yl)methanol (109 mg), potassium tert-butoxide (93 mg) and DME (5 ml) was heated at 120° C. for 30 min under microwave irradiation. Additional potassium tert-butoxide (93 mg) and (5-fluorothiophen-2-yl)methanol (109 mg) in DME (0.5 ml) were added to the reaction mixture, and the resulting mixture was heated at 120° C. for further 30 min under microwave irradiation. The mixture was quenched with water and extracted with EtOAc/MeOH. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The resulting solid was crystallized from EtOH-IPA to give the title compound (120 mg) as an off-white solid.

MS (ESI+): [M+H]+ 396.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.85-0.94 (4H, m), 2.02-2.12 (1H, m), 2.48 (3H, s), 5.25 (2H, d, J=2.3 Hz), 6.05-6.13 (2H, m), 6.65-6.71 (1H, m), 7.01 (1H, t, J=3.6 Hz), 7.12 (1H, d, J=9.5 Hz), 7.44 (1H, d, J=9.5 Hz), 7.66 (1H, d, J=7.8 Hz), 8.37 (1H, s).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-fluorothiophen-2-yl)methoxy)pyridin-2(1H)-one

A mixture of 1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (400 mg), (5-fluorothiophen-2-yl)methanol (376 mg), tributylphosphine (1.07 ml), 1,1′-(azodicarbonyl)dipiperidine (1.08 g) and THF (40 ml) was stirred at 60° C. under a dry atmosphere (CaCl 2 tube) for 3 h. After solvent was evaporated, the residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by preparative HPLC (C18, mobile phase: H 2 O/CH 3 CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO 3 solution, and extracted with EtOAc. The organic layer was separated, dried over MgSO 4 and concentrated in vacuo to give the title compound (130 mg) as an off-white solid.

MS (ESI+): [M+H]+ 396.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.01-1.14 (4H, m), 2.23-2.31 (1H, m), 3.85 (3H, s), 5.17-5.28 (2H, m), 6.00-6.12 (2H, m), 6.64-6.73 (1H, m), 6.95-7.11 (2H, m), 7.49-7.54 (2H, m), 7.58 (1H, d, J=7.3 Hz).

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((5-(trifluoromethyl)thiophen-2-yl)methoxy)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (5-(trifluoromethyl)thiophen-2-yl)methanol (130 mg) and tributylphosphine (0.27 ml) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg) at 60° C., and the mixture was heated at the same temperature for 2 h. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated, and purified by NH silica gel column chromatography (hexane/EtOAc), followed by silica gel column chromatography (EtOAc/MeOH). The resulting solid was purified by preparative HPLC (C18, mobile phase: H 2 O/CH 3 CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO 3 solution, and extracted with EtOAc. The organic layer was separated, dried over MgSO 4 and concentrated in vacuo to give the title compound (32.0 mg) as a white solid.

MS (ESI+): [M+H]+ 446.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.84-0.98 (4H, m), 2.02-2.12 (1H, m), 2.48 (3H, s), 5.46 (2H, s), 6.09 (1H, d, J=2.5 Hz), 6.14 (1H, dd, J=2.6, 7.5 Hz), 7.12 (1H, dd, J=1.7, 9.5 Hz), 7.39 (1H, d, J=2.8 Hz), 7.44 (1H, d, J=9.4 Hz), 7.65-7.71 (2H, m), 8.38 (1H, s).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-(trifluoromethyl)thiophen-2-yl)methoxy)pyridin-2(1H)-one

To a mixture of 1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (5-(trifluoromethyl)thiophen-2-yl)methanol (130 mg) and tributylphosphine (0.26 ml) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg), and the mixture was stirred at 60° C. overnight. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOAc-EtOH to give the title compound (55.7 mg) as an off-white solid.

MS (ESI+): [M+H]+ 446.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.99-1.14 (4H, m), 2.22-2.31 (1H, m), 3.85 (3H, s), 5.45 (2H, s), 6.06 (1H, d, J=2.5 Hz), 6.10 (1H, dd, J=2.7, 7.5 Hz), 7.05 (1H, dd, J=1.8, 8.5 Hz), 7.38 (1H, d, J=2.8 Hz), 7.49-7.54 (2H, m), 7.60 (1H, d, J=7.5 Hz), 7.69 (1H, d, J=2.8 Hz).

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((5-(trifluoromethyl)thiophen-2-yl)methoxy)pyridin-2(1H)-one hydrochloride

4 M HCl in EtOAc (0.714 ml) was added to a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((5-(trifluoromethyl)thiophen-2-yl)methoxy)pyridin-2(1H)-one (1.27 g) in EtOAc (25 ml) at room temperature. The mixture was stirred at room temperature for 2 h. The resulting suspension was filtered and the precipitate was washed with EtOAc. The precipitate was crystallized from EtOH-IPE to give the title compound (0.39 g) as a white solid.

MS (ESI+): [M+H]+ 446.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.88-1.02 (2H, m), 1.05-1.24 (2H, m), 2.23 (1H, brs), 2.55 (3H, s), 5.48 (2H, s), 6.14 (1H, d, J=2.5 Hz), 6.23 (1H, d, J=5.5 Hz), 7.40 (1H, brs), 7.67-7.74 (2H, m), 7.73-7.87 (2H, m), 8.86 (1H, brs).

4-((5-Chloro-3-fluoropyridin-2-yl)methoxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one and (5-chloro-3-fluoropyridin-2-yl)methanol.

MS (ESI+): [M+H]+ 425.3.

1-(2,3-Dimethylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

To a mixture of 6-iodo-2,3-dimethylimidazo[1,2-a]pyridine (204 mg), 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (150 mg), potassium carbonate (283 mg) and dioxane (15 ml) were added CuI (51 mg) and trans-N,N′-dimethyl-cyclohexane-1,2-diamine (38 mg), and the mixture was heated at 110° C. in a sealed tube for 16 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to afford the title compound (75 mg) as an off-white solid.

MS (ESI+): [M+H]+ 363.8.

1 H NMR (400 MHz, DMSO-d 6 ): δ 2.33 (3H, s), 2.39 (3H, s), 5.14 (2H, s), 6.01 (1H, d, J=2.6 Hz), 6.13 (1H, dd, J=2.7, 7.6 Hz), 7.13 (1H, dd, J=1.9, 9.5 Hz), 7.26 (2H, t, J=8.8 Hz), 7.46 (1H, d, J=9.4 Hz), 7.52 (2H, dd, J=5.6, 8.5 Hz), 7.66 (1H, d, J=7.6 Hz), 8.38 (1H, d, J=1.3 Hz).

4-(Benzyloxy)-1-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a stirred degassed mixture of 6-iodo-2,3-dimethylimidazo[1,2-a]pyridine (149 mg), 4-(benzyloxy)pyridin-2(1H)-one (100 mg), potassium carbonate (206 mg) and dioxane (10 ml) were added CuI (19 mg) and trans-N,N′-dimethyl-cyclohexane-1,2-diamine (14 mg), and the mixture was heated at 110° C. in a sealed tube for 16 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to afford the title compound (59 mg) as an off-white solid.

MS (ESI+): [M+H]+ 345.8.

1 H NMR (400 MHz, DMSO-d 6 ): δ 2.33 (3H, s), 2.39 (3H, s), 5.16 (2H, s), 6.01 (1H, d, J=2.6 Hz), 6.14 (1H, dd, J=2.6, 7.5 Hz), 7.13 (1H, dd, J=1.9, 9.4 Hz), 7.34-7.48 (6H, m), 7.66 (1H, d, J=7.6 Hz), 8.39 (1H, s).

4-((5-Chlorothiophen-3-yl)methoxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chlorothiophen-3-yl)methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM (100 ml), washed with water and brine successively, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to afford the title compound (90 mg) as a white solid.

MS (ESI+): [M+H]+ 412.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.88-0.92 (4H, m), 2.05-2.09 (1H, m), 2.47 (3H, s), 5.06 (2H, s), 6.01 (1H, d, J=2.6 Hz), 6.10 (1H, dd, J=2.7, 7.6 Hz), 7.11 (1H, dd, J=1.9, 9.5 Hz), 7.20 (1H, d, J=1.7 Hz), 7.43 (1H, d, J=9.4 Hz), 7.56 (1H, d, J=1.2 Hz), 7.65 (1H, d, J=7.7 Hz), 8.36 (1H, d, J=1.3 Hz).

4-((5-Chlorothiophen-3-yl)methoxy)-1-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

A) 1-(2,3-Dimethylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one

To a stirred solution of 4-(benzyloxy)-1-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (500 mg) in TFA (21 ml) was added anisole (7 ml), and the reaction mixture was heated at 130° C. for 4 h. The mixture was concentrated in vacuo to afford the title compound (310 mg) as a white solid.

MS (ESI+): [M+H]+ 256.2.

B) 4-((5-Chlorothiophen-3-yl)methoxy)-1-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a solution of 1-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chlorothiophen-3-yl)methanol (174 mg) and tributylphosphine (358 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (447 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM (100 ml), washed with water and brine successively, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to afford the title compound (90 mg) as a white solid.

MS (ESI+): [M+H]+ 385.8.

1 H NMR (400 MHz, DMSO-d 6 ): δ 2.32 (3H, s), 2.39 (3H, s), 5.06 (2H, s), 6.01 (1H, d, J=2.4 Hz), 6.11 (1H, dd, J=2.4, 7.5 Hz), 7.12 (1H, dd, J=1.6, 9.6 Hz), 7.20 (1H, s), 7.46 (1H, d, J=9.4 Hz), 7.56 (1H, s), 7.66 (1H, d, J=7.5 Hz), 8.38 (1H, s).

4-((5-Chlorothiophen-2-yl)methoxy)-1-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a solution of 1-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chlorothiophen-2-yl)methanol (174 mg) and tributylphosphine (358 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (447 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM (100 ml), washed with water and brine successively, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to afford the title compound (56 mg) as a white solid.

MS (ESI+): [M+H]+ 386.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 2.32 (3H, s), 2.39 (3H, s), 5.30 (2H, s), 6.06 (1H, d, J=2.6 Hz), 6.10 (1H, dd, J=2.6, 7.5 Hz), 7.08 (1H, d, J=3.8 Hz), 7.13 (1H, dd, J=1.9, 9.8 Hz), 7.17 (1H, d, J=3.8 Hz), 7.46 (1H, d, J=9.6 Hz), 7.67 (1H, d, J=7.5 Hz), 8.38 (1H, d, J=1.4 Hz).

4-(Benzyloxy)-1-(2-ethyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

A) N-(5-Iodo-1-(3-oxopentan-2-yl)pyridin-2(1H)-ylidene)-4-methylbenzenesulfonamide

To a stirred solution of N-(5-iodopyridin-2-yl)-4-methylbenzenesulfonamide (3 g) and 2-bromopentan-3-one (3.3 g) in THF (50 ml) was added N,N-diisopropylethylamine (5.6 ml) at 0° C., and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, poured into saturated NaHCO 3 solution and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 , concentrated in vacuo and purified by silica gel column chromatography (hexane/EtOAc) to afford the title compound (1.6 g) as a yellow solid.

MS (ESI+): [M+H]+ 459.0.

B) 2-Ethyl-6-iodo-3-methylimidazo[1,2-a]pyridine

To a stirred solution of N-(5-iodo-1-(3-oxopentan-2-yl)pyridin-2(1H)-ylidene)-4-methylbenzenesulfonamide (4 g) in THF (50 ml) was added trifluoroacetic anhydride (10 ml) at 0° C., and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, poured into saturated aqueous NaHCO 3 solution and extracted with DCM. The extract was washed with brine, dried over Na 2 SO 4 , concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to afford the title compound (1.3 g) as a yellow solid.

MS (ESI+): [M+H]+ 286.6.

C) 4-(Benzyloxy)-1-(2-ethyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 163 using 4-(benzyloxy)pyridin-2(1H)-one and 2-ethyl-6-iodo-3-methylimidazo[1,2-a]pyridine.

MS (ESI+): [M+H]+ 359.8.

4-((4-Chlorothiophen-2-yl)methoxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (4-chlorothiophen-2-yl)methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (400 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM (100 ml), washed with water and brine successively, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to afford the title compound (12 mg) as a white solid.

MS (ESI+): [M+H]+ 412.2.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.87-0.92 (4H, m), 2.05-2.09 (1H, m), 2.47 (3H, s), 5.33 (2H, s), 6.06 (1H, d, J=2.7 Hz), 6.11 (1H, dd, J=2.8, 7.3 Hz), 7.11 (1H, dd, J=1.9, 9.4 Hz), 7.28 (1H, d, J=1.3 Hz), 7.43 (1H, d, J=9.3 Hz), 7.64-7.65 (1H, m), 7.67 (1H, s), 8.37 (1H, d, J=1.6 Hz).

1-(2-Ethyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 163 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 2-ethyl-6-iodo-3-methylimidazo[1,2-a]pyridine.

MS (ESI+): [M+H]+ 378.2.

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorophenoxy)methyl)pyridin-2(1H)-one

A) Methyl 2-oxo-1,2-dihydropyridine-4-carboxylate

To a stirred solution of 2-hydroxypyridine-4-carboxylic acid (5.0 g) in MeOH (50 ml) was added acetyl chloride (26 ml) dropwise at 0° C. over 15 min. The reaction mixture was slowly warmed to room temperature, and stirred for 20 h. The reaction mixture was concentrated in vacuo, and diluted with EtOAc and water. The organic layer was washed with saturated NaHCO 3 solution, concentrated in vacuo, and purified by column chromatography (MeOH/DCM) to afford the title compound (3.5 g) as an off-white solid.

MS (ESI+): [M+H]+ 154.0.

B) Methyl 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-2-oxo-1,2-dihydropyridine-4-carboxylate

To a mixture of 2-cyclopropyl-6-iodo-3-methylimidazo[1,2-a]pyridine (1.9 g), methyl 2-oxo-1,2-dihydropyridine-4-carboxylate (1.0 g), potassium carbonate (901 mg) and dioxane (30 ml) were added CuI (248 mg) and trans-N,N′-dimethyl-cyclohexane-1,2-diamine (308 mg), and the mixture was heated at 110° C. in a sealed tube for 16 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and diluted with a mixture of DCM and MeOH. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (550 mg) as a brown solid.

MS (ESI+): [M+H]+ 323.8.

C) 1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-(hydroxymethyl)pyridin-2(1H)-one

To a solution of methyl 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-2-oxo-1,2-dihydropyridine-4-carboxylate (600 mg) in DCM (10 ml) was added diisobutylaluminum hydride (1.76 M in toluene, 2.1 ml) at 78° C. The mixture was stirred at same temperature for 3 h, and allowed to warm to room temperature for 4 h. The mixture was quenched with a mixture of MeOH and water, and filtered through celite. The filtrate was concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (200 mg) as a brown solid.

MS (ESI+): [M+H]+ 296.0.

D) 1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorophenoxy)methyl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-(hydroxymethyl)pyridin-2(1H)-one (150 mg), 4-fluorophenol (85 mg) and tributylphosphine (307 mg) in THF (20 ml) was added 1,1′-(azodicarbonyl)dipiperidine (386 mg), and the mixture was stirred at 60° C. for 5 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and diluted with DCM. The mixture was washed with water and brine successively, dried over Na 2 SO 4 , concentrated in vacuo and purified by column chromatography (MeOH/DCM) followed by preparative HPLC to afford the title compound (24 mg) as a white solid.

MS (ESI+): [M+H]+ 390.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.88-0.92 (4H, m), 2.07 (1H, m), 5.06 (2H, s), 6.36 (1H, d, J=7.0 Hz), 6.54 (1H, s), 7.04-7.07 (2H, m), 7.14-7.18 (3H, m), 7.45 (1H, d, J=9.4 Hz), 7.74 (1H, d, J=7.0 Hz), 8.43 (1H, s). 3H was overlapped with DMSO peak, and not detected.

4-((5-Chlorothiophen-2-yl)methoxy)-1-(2-ethyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

A) 1-(2-Ethyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one

The title compound was obtained in an analogous manner to step A in example 165 using 4-(benzyloxy)-1-(2-ethyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one.

MS (ESI+): [M+H]+ 270.0.

B) 4-((5-Chlorothiophen-2-yl)methoxy)-1-(2-ethyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 75 using 1-(2-ethyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one and (5-chlorothiophen-2-yl)methanol.

MS (ESI+): [M+H]+ 270.0.

4-((5-Chlorothiophen-3-yl)methoxy)-1-(2-ethyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-ethyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chlorothiophen-3-yl)methanol (165 mg) and tributylphosphine (340 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (424 mg), and the mixture was stirred at 60° C. for 5 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and diluted with DCM. The mixture was washed with water and brine successively, dried over Na 2 SO 4 , concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (60 mg) as a white solid.

MS (ESI+): [M+H]+ 270.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.22 (3H, t, J=7.5 Hz), 2.39 (3H, s), 2.69 (2H, q, J=7.5 Hz), 5.06 (2H, s), 6.01 (1H, d, J=2.6 Hz), 6.11 (1H, dd, J=2.7, 7.6 Hz), 7.13 (1H, dd, J=1.9, 9.5 Hz), 7.20 (1H, d, J=1.7 Hz), 7.48 (1H, d, J=9.4 Hz), 7.56 (1H, s), 7.66 (1H, d, J=7.6 Hz), 8.38 (1H, d, J=1.5 Hz).

4-((4-Chlorobenzyl)oxy)-1-(2-(2-(2-hydroxypropan-2-yl)cyclopropyl)-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

A) 6-Iodo-3-methylimidazo[1,2-a]pyridine-2-carbaldehyde

To a stirred solution of ethyl 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylate (2.0 g) in DCM (40 ml) was added diisobutylaluminum hydride (1.0 M solution in toluene, 8 ml) at −78° C., and the resultant mixture was stirred at same temperature for 3 h. The reaction mixture was quenched with MeOH (10 ml) and 2 M HCl (15 ml), and basified with saturated aqueous NaHCO 3 solution (20 ml) at 0° C. The mixture was extracted with DCM, washed with brine, dried over Na 2 SO 4 , concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (1.2 g) as a light yellow solid.

MS (ESI+): [M+H]+ 287.0.

B) 2-Ethenyl-6-iodo-3-methylimidazo[1,2-a]pyridine

To a stirred suspension of methyltriphenylphosphonium bromide (3.1 g) in THF (20 ml) was added NaH (60% in oil, 336 mg) at 0° C. The reaction mixture was then stirred at room temperature for 16 h. A solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carbaldehyde (500 mg) in THF (10 ml) was added to the reaction mixture at 0° C., and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with ice-water (20 ml) and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 , concentrated in vacuo and purified by column chromatography (hexane/EtOAc) to afford the title compound (350 mg) as an off-white solid.

MS (ESI+): [M+H]+ 284.8.

C) Ethyl 2-(6-iodo-3-methylimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxylate

To a stirred solution of 2-ethenyl-6-iodo-3-methylimidazo[1,2-a]pyridine (680 mg) in xylene (20 ml) was added ethyl diazoacetate (1.5 ml) at room temperature. The reaction mixture was heated at reflux for 5 h. The resulting reaction mixture was then cooled to room temperature, concentrated in vacuo, and purified by preparative HPLC to afford the title compound (200 mg) as a yellow solid.

MS (ESI+): [M+H]+ 371.0.

D) Ethyl 2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-3-methylimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxylate

To a mixture of ethyl 2-(6-iodo-3-methylimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxylate (280 mg), 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (140 mg), potassium carbonate (243 mg) and dioxane (2 ml) were added CuI (57 mg) and trans-N,N′-dimethyl-cyclohexane-1,2-diamine (43 mg), and the mixture was heated at 110° C. for 12 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The resulting residue was diluted with DCM, washed with brine, dried over Na 2 SO 4 , concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (250 mg) as a white solid.

MS (ESI+): [M+H]+ 478.4.

E) 4-((4-Chlorobenzyl)oxy)-1-(2-(2-(2-hydroxypropan-2-yl)cyclopropyl)-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a stirred solution of ethyl 2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-3-methylimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxylate (250 mg) in THF (2 ml) was added methylmagnesium bromide (3.0 M solution in ether, 1.8 ml) at 0° C., and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was then quenched with saturated NH 4 Cl solution, and extracted with DCM. The extract was washed with brine, dried over Na 2 SO 4 , concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (7 mg) as an off-white solid.

MS (ESI+): [M+H]+ 464.0.

2-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-3-methylimidazo[1,2-a]pyridin-2-yl)cyclopropanecarbonitrile

A) (2E)-3-(6-Iodo-3-methylimidazo[1,2-a]pyridin-2-yl)prop-2-enenitrile

To a stirred suspension of cyanomethylphosphonic acid diethyl ester (619 mg) in THF (2 ml) was added NaH (60% in oil, 144 mg) at 0° C., and the mixture was stirred at same temperature for 16 h. A solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carbaldehyde (250 mg) in THF (2 ml) was added, and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with saturated NH 4 Cl solution, and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 , concentrate, and purified by column chromatography (hexane/EtOAc) to afford the title compound (120 mg) as a pale yellow solid.

MS (ESI+): [M+H]+ 464.0.

B) 2-(6-Iodo-3-methylimidazo[1,2-a]pyridin-2-yl)cyclopropanecarbonitrile

To a stirred suspension of NaH (60% in oil, 270 mg) in DMF (5 ml) was added trimethylsulfoxonium iodide (1.37 g) at room temperature, and the mixture was stirred for 3 h. A solution of (2E)-3-(6-iodo-3-methylimidazo[1,2-a]pyridin-2-yl)prop-2-enenitrile (600 mg) in DMF (1 ml) was added, and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with saturated NH 4 Cl solution and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 , concentrated in vacuo, and purified by column chromatography (hexane/EtOAc) followed by preparative HPLC to afford the title compound (40 mg) as an off-white solid.

MS (ESI+): [M+H]+ 324.0.

C) 2-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-3-methylimidazo[1,2-a]pyridin-2-yl)cyclopropanecarbonitrile

To a mixture of 2-(6-iodo-3-methylimidazo[1,2-a]pyridin-2-yl)cyclopropanecarbonitrile (26 mg), 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (45 mg), potassium carbonate (58 mg) and dioxane (2 ml) were added CuI (7 mg) and trans-N,N′-dimethyl-cyclohexane-1,2-diamine (5 mg), and the mixture was heated at 110° C. for 16 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM, washed with brine, dried over Na 2 SO 4 , concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (15 mg) as an off-white solid.

MS (ESI+): [M+H]+ 431.2.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.23-1.65 (2H, m), 2.07-2.11 (1H, m), 2.94-2.99 (1H, m), 5.17 (2H, s), 6.00 (1H, d, J=2.4 Hz), 6.15 (1H, dd, J=2.4, 7.6 Hz), 7.19 (1H, d, J=9.5 Hz), 7.46-7.49 (5H, m), 7.66 (1H, d, J=7.6 Hz), 8.44 (1H, s). 3H was overlapped with DMSO peak, and not detected.

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((5-fluoro-2-thienyl)methoxy)pyridin-2(1H)-one

A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (285 mg), (5-fluorothiophen-2-yl)methanol (109 mg), potassium tert-butoxide (93 mg) and DME (5 ml) was heated at 120° C. for 30 min under microwave irradiation. Additional potassium tert-butoxide (93 mg) and (5-fluorothiophen-2-yl)methanol (109 mg) in DME (0.5 ml) were added to the reaction mixture, and the resulting mixture was heated at 120° C. for further 30 min under microwave irradiation. The mixture was quenched with water and extracted with EtOAc/MeOH. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was crystallized from EtOH-IPA to give the title compound (120 mg) as an off-white solid.

MS (ESI+): [M+H]+ 396.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.85-0.94 (4H, m), 2.02-2.12 (1H, m), 2.48 (3H, s), 5.25 (2H, d, J=2.3 Hz), 6.05-6.13 (2H, m), 6.65-6.71 (1H, m), 7.01 (1H, t, J=3.6 Hz), 7.12 (1H, d, J=9.5 Hz), 7.44 (1H, d, J=9.5 Hz), 7.66 (1H, d, J=7.8 Hz), 8.37 (1H, s).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-fluorothiophen-2-yl)methoxy)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (127 mg), (5-fluorothiophen-2-yl)methanol (40 mg) and tributylphosphine (182 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (227 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine successively, dried over Na 2 SO 4 , concentrated in vacuo and purified by column chromatography (MeOH/DCM) followed by preparative HPLC to afford the title compound (6 mg) as a white solid.

MS (ESI+): [M+H]+ 396.0.

1 H NMR (400 MHz, CD 3 OD): δ 1.14-1.17 (4H, m), 2.23 (1H, m), 3.90 (3H, s), 5.22 (2H, s), 6.14 (1H, s), 6.23 (1H, d, J=5.8

Hz), 6.49 (1H, s), 6.90 (1H, s), 7.15 (1H, d, J=7.7 Hz), 7.49 (1H, s), 7.59 (2H, t, J=8.4 Hz).

4-((5-Bromo-3-thienyl)methoxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (87 mg), (5-bromo-3-thienyl)methanol (119 mg) and tributylphosphine (188 mg) in THF (4 ml) was added 1,1′-(azodicarbonyl)dipiperidine (234 mg), and the reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was then cooled to room temperature, concentrated, and purified by silica gel column chromatography (hexane/EtOAc then MeOH/EtOAc). The resulting solid was recrystallized from EtOH/hexane to give the title compound (38 mg) as a white solid.

MS (ESI+): [M+H]+ 456.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.82-0.98 (4H, m), 2.07 (1H, t, J=5.3 Hz), 2.48 (3H, brs), 5.09 (2H, s), 6.01 (1H, d, J=2.5 Hz), 6.11 (1H, dd, J=2.6, 7.7 Hz), 7.11 (1H, d, J=9.3 Hz), 7.30 (1H, s), 7.43 (1H, d, J=9.4 Hz), 7.61-7.71 (2H, m), 8.37 (1H, s).

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((5-(difluoromethyl)-2-thienyl)methoxy)pyridin-2(1H)-one

A) Methyl 5-(difluoromethyl)thiophene-2-carboxylate

To a solution of methyl 5-formylthiophene-2-carboxylate (4.15 g) in toluene (100 ml) was added dropwise DAST (4.83 ml) at 0° C., and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated NaHCO 3 solution and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (2.23 g) as a pale yellow solid.

1 H NMR (400 MHz, CDCl 3 ): δ 3.91 (3H, s), 6.83 (1H, t, J=55.8 Hz), 7.27 (1H, brs), 7.69-7.77 (1H, m).

B) (5-(Difluoromethyl)-2-thienyl)methanol

To a solution of methyl 5-(difluoromethyl)thiophene-2-carboxylate (2.23 g) in THF (60 ml)-MeOH (15 ml) was added NaBH 4 (2.20 g) at room temperature, and the reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH 4 Cl solution, and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.94 g) as a pale yellow oil.

1 H NMR (400 MHz, CDCl 3 ): δ 1.86 (1H, t, J=6.0 Hz), 4.85 (2H, d, J=5.5 Hz), 6.62-6.99 (2H, m), 7.16 (1H, brs).

C) 1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((5-(difluoromethyl)-2-thienyl)methoxy)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (350 mg), (5-(difluoromethyl)-2-thienyl)methanol (409 mg) and tributylphosphine (755 mg) in THF (12 ml) was added 1,1′-(azodicarbonyl)dipiperidine (942 mg), and the reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was cooled to room temperature, concentrated and purified by silica gel column chromatography (hexane/EtOAc then MeOH/EtOAc). The resulting solid was recrystallized from EtOH-hexane to give the title compound (80 mg) as a white solid.

MS (ESI+): [M+H]+ 428.4.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.83-0.94 (4H, m), 2.07 (1H, brs), 5.42 (2H, s), 6.04-6.17 (2H, m), 7.12 (1H, d, J=9.3 Hz), 7.31 (1H, d, J=5.3 Hz), 7.43 (1H, d, J=9.5 Hz), 7.67 (1H, d, J=7.5 Hz), 8.01 (2H, s), 8.38 (1H, s).

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((2-(trifluoromethyl)-1,3-thiazol-4-yl)methoxy)pyridin-2(1H)-one

A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (80 mg), (2-(trifluoromethyl)-1,3-thiazol-4-yl)methanol (51.1 mg), potassium tert-butoxide (78 mg) and toluene (2 ml) was heated at 100° C. for 1 h. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (16.2 mg) as a white solid.

MS (ESI+): [M+H]+ 447.4.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.85-0.96 (4H, m), 2.03-2.13 (1H, m), 2.48 (3H, brs), 5.33 (2H, s), 6.12 (1H, s), 6.16 (1H, d, J=7.7 Hz), 7.12 (1H, d, J=9.4 Hz), 7.44 (1H, d, J=9.4 Hz), 7.68 (1H, d, J=7.7 Hz), 8.36 (2H, d, J=16.8 Hz).

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((5-(trifluoromethyl)-2-furyl)methoxy)pyridin-2(1H)-one

A) 4-Bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (3.0 g) in DMF (25 ml) was added phosphorus oxybromide (2.17 ml) at room temperature, and the mixture was stirred at 110° C. for 1 h. The mixture was diluted with EtOAc and water, quenched with saturated NaHCO 3 solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc) to give the title compound (0.70 g) as a pale yellow solid.

MS (ESI+): [M+H]+ 344.0.

B) 1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((5-(trifluoromethyl)-2-furyl)methoxy)pyridin-2(1H)-one

To a suspension of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (120 mg) and (5-(trifluoromethyl)furan-2-yl)methanol (87 mg) in toluene (2 ml) was added potassium tert-butoxide (117 mg) at room temperature, and the mixture was stirred at 100° C. for 1 h. The mixture was quenched with water, and the precipitate was collected by filtration and washed with IPE to give the title compound (75 mg) as a yellow solid.

MS (ESI+): [M+H]+ 430.1

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.84-0.95 (4H, m), 2.02-2.12 (1H, m), 2.48 (3H, brs), 5.24 (2H, s), 6.09-6.18 (2H, m), 6.92 (1H, d, J=2.6 Hz), 7.08-7.16 (1H, m), 7.28 (1H, brs), 7.44 (1H, d, J=9.4 Hz), 7.67 (1H, d, J=7.7 Hz), 8.38 (1H, s).

4-(((5-Chloro-2-thienyl)methyl)amino)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (30 mg), 1-(5-chloro-2-thienyl)methanamine (20 mg), tris(dibenzylideneacetone)dipalladium(0) (2.0 mg), cesium carbonate (57 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3 mg) and DMA (0.4 ml) was heated at 120° C. for 1 h under microwave irradiation. To this mixture was added water, and the precipitate was collected by filtration. The resulting solid was recrystallized from EtOAc-hexane-EtOH to give the title compound (8.6 mg) as a yellow solid.

MS (ESI+): [M+H]+ 411.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.83-0.94 (4H, m), 2.01-2.11 (1H, m), 2.46 (3H, s), 4.44 (2H, d, J=5.9 Hz), 5.33 (1H, s), 5.89 (1H, d, J=5.8 Hz), 6.95-7.02 (2H, m), 7.07 (1H, d, J=9.5 Hz), 7.32-7.46 (3H, m), 8.27 (1H, s).

4-(((5-Chloro-2-thienyl)methyl)(methyl)amino)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a suspension of 4-(((5-chloro-2-thienyl)methyl)amino)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (11.5 mg) in DMF (1 ml) was added NaH (60% in oil, 1.7 mg) at 0° C. After the reaction mixture was stirred at 0° C. for 10 min, iodomethane (2.61 μl) was added to the reaction mixture. The mixture was stirred at room temperature for 3 h. The mixture was quenched with water, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 and concentrated in vacuo. The residue was triturated with IPE, and the resulting solid was collected by filtration and washed with EtOAc-IPE to give the title compound (4.0 mg) as a pale yellow solid.

MS (ESI+): [M+H]+ 425.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.85-0.94 (4H, m), 2.02-2.10 (1H, m), 2.47 (3H, brs), 3.01 (3H, s), 4.75 (2H, s), 5.44 (1H, d, J=2.3 Hz), 6.18-6.26 (1H, m), 6.93 (1H, d, J=3.6 Hz), 7.02 (1H, d, J=3.6 Hz), 7.10 (1H, d, J=11.0 Hz), 7.40 (1H, d, J=9.4 Hz), 7.52 (1H, d, J=7.8 Hz), 8.31 (1H, s).

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((5-(trifluoromethyl)-3-thienyl)methoxy)pyridin-2(1H)-one

A) Methyl 5-iodothiophene-3-carboxylate

A mixture of 5-iodothiophene-3-carboxylic acid (3.48 g), iodomethane (2.92 g), potassium carbonate (2.84 g) and DMF (35 ml) was stirred at room temperature for 1 day. The reaction mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (3.62 g) as a white solid.

1 H NMR (400 MHz, CDCl 3 ): δ 3.86 (3H, s), 7.66 (1H, s), 8.08 (1H, s).

B) Methyl 5-(trifluoromethyl)thiophene-3-carboxylate

To a solution of methyl 5-iodothiophene-3-carboxylate (15.2 g), copper iodide (21.5 g) and hexamethylphosphoramide (50.6 g) in DMF (150 ml) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (54.3 g) at room temperature, and the reaction mixture was stirred at 80° C. under N 2 atmosphere for 5 h. The reaction mixture was then cooled to room temperature, neutralized with saturated NaHCO 3 solution and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by silica gel column chromatography (hexane/toluene) to give the title compound (9.39 g) as a colorless oil.

1 H NMR (400 MHz, CDCl 3 ): δ 3.89 (3H, s), 7.86 (1H, s), 8.23 (1H, d, J=1.0 Hz).

C) (5-(Trifluoromethyl)-3-thienyl)methanol

To a solution of methyl 5-(trifluoromethyl)thiophene-3-carboxylate (523 mg) in THF (1 ml)-MeOH (1 ml) was added NaBH 4 (2.2 g) at room temperature, and the reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was quenched with water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (449 mg) as a pale yellow oil.

1 H NMR (400 MHz, CDCl 3 ): δ 1.71 (1H, t, J=5.7 Hz), 4.70 (2H, d, J=5.6 Hz), 7.39 (1H, s), 7.43 (1H, s). D) 1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((5-(trifluoromethyl)-3-thienyl)methoxy)pyridin-2(1H)-one

A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (111 mg), (5-(trifluoromethyl)-3-thienyl)methanol (88 mg), potassium tert-butoxide (109 mg) and toluene (3 ml) was heated at 100° C. for 1 h. The reaction mixture was cooled to room temperature, poured into water and extracted with EtOAc-THF. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from IPA-IPE to give the title compound (47.5 mg) as a white solid.

MS (ESI+): [M+H]+ 446.4.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.83-0.99 (4H, m), 2.07 (1H, brs), 5.17 (2H, s), 6.05 (1H, s), 6.13 (1H, d, J=5.0 Hz), 7.12 (1H, d, J=9.9 Hz), 7.44 (1H, d, J=9.3 Hz), 7.67 (1H, d, J=7.5 Hz), 7.81 (1H, s), 8.07 (1H, s), 8.37 (1H, s).

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((5-(difluoromethyl)-3-thienyl)methoxy)pyridin-2 (1H)-one

A) Methyl 5-(difluoromethyl)thiophene-3-carboxylate

To a solution of methyl 5-formylthiophene-3-carboxylate (500 mg) in toluene (10 ml) was added dropwise DAST (947 mg), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated NaHCO 3 solution and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (213 mg) as a colorless oil.

1 H NMR (400 MHz, CDCl 3 ): δ 3.88 (3H, s), 6.82 (1H, t, J=55.8 Hz), 7.70 (1H, d, J=1.1 Hz), 8.20 (1H, s).

B) (5-(Difluoromethyl)-3-thienyl)methanol

To a solution of methyl 5-(difluoromethyl)thiophene-3-carboxylate (267 mg) in THF (5 ml)-MeOH (1 ml) was added NaBH 4 (263 mg) at room temperature, and the reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was quenched with water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (192 mg) as a colorless oil.

1 H NMR (400 MHz, CDCl 3 ): δ 1.66 (1H, t, J=5.8 Hz), 4.69 (2H, d, J=5.8, Hz), 6.81 (1H, t, J=56.1 Hz), 7.29 (1H, brs), 7.35 (1H, s).

C) 1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((5-(difluoromethyl)-3-thienyl)methoxy)pyridin-2(1H)-one

A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (100 mg), (5-(difluoromethyl)-3-thienyl)methanol (88 mg), potassium tert-butoxide (109 mg) and toluene (3 ml) was heated at 100° C. for 1 h. The reaction mixture was then cooled to room temperature, poured into water and extracted with EtOAc-THF. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from IPA-IPE to give the title compound (64.1 mg) as a white solid.

MS (ESI+): [M+H]+ 428.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.90 (4H, t, J=7.5 Hz), 2.00-2.13 (1H, m), 2.48 (3H, brs), 5.15 (2H, s), 6.04 (1H, d, J=2.4 Hz), 6.12 (1H, dd, J=7.8, 2.6 Hz), 7.12 (1H, d, J=9.5 Hz), 7.17-7.47 (2H, m), 7.55 (1H, s), 7.66 (1H, d, J=7.7 Hz), 7.91 (1H, s), 8.37 (1H, s).

Reference Example 185

4-((4-Chlorobenzyl)oxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyrazin-6-yl)pyridin-2(1H)-one

A) N-(5-Bromo-1-(1-cyclopropyl-1-oxopropan-2-yl)pyrazin-2(1H)-ylidene)-4-methylbenzenesulfonamide

To a solution of N-(5-bromopyrazin-2-yl)-4-methylbenzenesulfonamide (1.73 g) in DMF (20 ml) was added NaH (60% in oil, 0.316 g) at 0° C., and the mixture was stirred at room temperature for 30 min. To the mixture was added 2-bromo-1-cyclopropylpropan-1-one (1.87 g) at room temperature, and the mixture was stirred overnight. The mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO 4 , concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.02 g) as a solid.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.74-1.00 (4H, m), 1.71 (3H, d, J=7.3 Hz), 2.21-2.29 (1H, m), 2.36 (3H, s), 5.63 (1H, d, J=7.3 Hz), 7.34 (2H, d, J=8.0 Hz), 7.69 (2H, d, J=8.2 Hz), 8.31 (1H, s), 8.76 (1H, s).

B) 6-Bromo-2-cyclopropyl-3-methylimidazo[1,2-a]pyrazine

To a solution of N-(5-bromo-1-(1-cyclopropyl-1-oxopropan-2-yl)pyrazin-2(1H)-ylidene)-4-methylbenzenesulfonamide (1.24 g) in THF (10 ml) was added trifluoroacetic anhydride (1.23 g) at 0° C., and the mixture was heated at 60° C. for 3 h. The mixture was partitioned between EtOAc and saturated NaHCO 3 solution, and the organic layer was washed with 1 M NaOH and brine successively, dried over MgSO 4 , concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (593 mg) as pale yellow crystals.

MS (ESI+): [M+H]+ 252.2.

C) 4-((4-Chlorobenzyl)oxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyrazin-6-yl)pyridin-2(1H)-one

A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (26.2 mg), 6-bromo-2-cyclopropyl-3-methylimidazo[1,2-a]pyrazine (42.1 mg), N,N′-dimethyl-1,2-ethanediamine (19.63 mg), CuI (21.2 mg), potassium carbonate (46.2 mg) and DMSO (1 ml) was heated at 150° C. for 1 h under microwave irradiation. The mixture was poured into 28% NH 3 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , concentrated in vacuo, and purified by column chromatography (hexane/EtOAc) to give the title compound (19.1 mg) as pale yellow crystals.

MS (ESI+): [M+H]+ 407.4.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.92-1.04 (4H, m), 2.14-2.24 (1H, m), 2.54 (3H, s), 5.18 (2H, s), 6.01 (1H, d, J=2.4 Hz), 6.17 (1H, dd, J=2.6, 7.7 Hz), 7.50 (4H, s), 7.78 (1H, d, J=7.7 Hz), 8.68 (1H, s), 8.83 (1H, s).

4-((4-Chlorobenzyl)amino)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (80 mg), 4-chlorobenzylamine (49.4 mg), xantphos (10.8 mg), tris(dibenzylideneacetone)dipalladium(0) (5.3 mg), cesium carbonate (151 mg) and DMA (2 ml) was heated at 120° C. for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature, poured into water and extracted with EtOAc-THF. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (19.1 mg) as a white solid.

MS (ESI+): [M+H]+ 405.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.79-0.98 (4H, m), 1.98-2.13 (1H, m), 2.46 (3H, s), 4.30 (2H, d, J=5.9 Hz), 5.18 (1H, brs), 5.92 (1H, dd, J=2.2, 7.6 Hz), 7.06 (1H, dd, J=1.8, 9.6 Hz), 7.31-7.47 (7H, m), 8.25 (1H, s).

Reference Example 187

4-(Benzyloxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyrazin-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in reference example 185 using 4-(benzyloxy)pyridin-2(1H)-one and 6-bromo-2-cyclopropyl-3-methylimidazo[1,2-a]pyrazine:

MS (ESI+): [M+H]+ 373.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.89-1.06 (4H, m), 2.13-2.25 (1H, m), 2.54 (3H, s), 5.18 (2H, s), 6.01 (1H, d, J=2.5 Hz), 6.17 (1H, dd, J=2.6, 7.7 Hz), 7.30-7.51 (5H, m), 7.77 (1H, d, J=7.8 Hz), 8.69 (1H, s), 8.83 (1H, s).

Reference Example 188

4-((E)-2-(4-Chlorophenyl)ethenyl)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (178 mg), (E)-(4-chlorostyryl)boronic acid (189 mg), potassium carbonate (214 mg), PdCl 2 (dppf) (18.9 mg), THF (3 ml) and water (1 ml) was heated at 70° C. under N 2 atmosphere overnight. The mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO 4 , concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (80 mg) as a solid.

MS (ESI+): [M+H]+ 402.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.86-0.98 (4H, m), 2.02-2.16 (1H, m), 3.28 (3H, brs), 6.60 (1H, s), 6.74 (1H, d, J=7.4 Hz), 7.14-7.28 (2H, m), 7.42-7.57 (4H, m), 7.66-7.78 (3H, m), 8.45 (1H, s).

4-((2-Bromo-1,3-thiazol-4-yl)methoxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (239 mg), (2-bromothiazol-4-yl)methanol (330 mg) and triphenylphosphine (669 mg) in THF (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (597 mg), and the mixture was stirred at room temperature for 3 h. The mixture was diluted with EtOAc, washed with water and brine successively, concentrated in vacuo, and purified by silica gel column chromatography (EtOAc/MeOH) to give the title compound (185 mg) as a white solid.

MS (ESI+): [M+H]+ 457.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.85-0.96 (4H, m), 2.02-2.12 (1H, m), 2.48 (3H, brs), 5.19 (2H, s), 6.08 (1H, d, J=2.5 Hz), 6.13 (1H, dd, J=2.5, 7.5 Hz), 7.12 (1H, dd, J=1.6, 9.4 Hz), 7.44 (1H, d, J=9.4 Hz), 7.67 (1H, d, J=7.7 Hz), 7.91 (1H, s), 8.38 (1H, s).

4-((4-tert-Butylbenzyl)oxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (200 mg) in DMF (3 ml) were added 1-(bromomethyl)-4-(tert-butyl)benzene (178 mg) and potassium carbonate (197 mg) at room temperature, and the mixture was stirred for 17 h. The mixture was poured into water, and the resultant solid was collected by filtration. The solid was recrystallized from acetone to give the title compound (143 mg) as white crystals.

MS (ESI+): [M+H]+ 428.4.

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-isopropylbenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 190 using 1-(bromomethyl)-4-isopropylbenzene and 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-ya)-4-hydroxypyridin-2(1H)-one.

MS (ESI+): [M+H]+ 414.4.

4-((4-Bromobenzyl)oxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (500 mg) in THF (5 ml) were added p-bromobenzyl alcohol (332 mg), (E)-bis(2-methoxyethyl)diazene-1,2-dicarboxylate (541 mg) and triphenylphosphine (606 mg), and the mixture was stirred at room temperature for 16 h. The mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO 4 , concentrated in vacuo, and purified by silica gel column chromatography (EtOAc/MeOH), followed by crystallization from hot EtOAc to give the title compound (502 mg) as white crystals.

MS (ESI+): [M+H]+ 450.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.82-0.96 (4H, m), 2.07 (1H, brs), 2.47 (3H, brs), 5.15 (2H, s), 5.99 (1H, d, J=2.4 Hz), 6.14 (1H, dd, J=2.5, 7.9 Hz), 7.06-7.15 (1H, m), 7.43 (3H, d, J=8.8 Hz), 7.59-7.69 (3H, m), 8.37 (1H, s).

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-(trifluoromethyl)-1,3-thiazol-2-yl)methoxy)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (49 mg), (4-(trifluoromethyl)-1,3-thiazol-2-yl)methanol (68.3 mg) and triphenylphosphine (137 mg) in THF (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (122 mg), and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (21.5 mg) as a white solid.

MS (ESI+): [M+H]+ 447.4.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.85-0.95 (4H, m), 2.07 (1H, brs), 2.48 (3H, brs), 5.57 (2H, s), 6.11 (1H, d, J=2.5 Hz), 6.21 (1H, dd, J=2.3, 7.5 Hz), 7.12 (1H, d, J=7.5 Hz), 7.44 (1H, d, J=9.4 Hz), 7.72 (1H, d, J=7.7 Hz), 8.40 (1H, s), 8.62 (1H, s).

4-((4-Bromo-1,3-thiazol-2-yl)methoxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (4-bromo-1,3-thiazol-2-yl)methanol (69 mg) and triphenylphosphine (140 mg) in THF (6 ml) was added bis(2-methoxyethyl) azodicarboxylate (125 mg), and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (37.9 mg) as a white solid.

MS (ESI+): [M+H]+ 457.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.77-1.01 (4H, m), 2.07 (1H, brs), 5.51 (2H, s), 6.08 (1H, brs), 6.19 (1H, d, J=7.8 Hz), 7.12 (1H, d, J=9.4 Hz), 7.44 (1H, d, J=8.8 Hz), 7.70 (1H, d, J=7.9 Hz), 7.96 (1H, s), 8.39 (1H, s).

Reference Example 195

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyrazin-6-yl)-4-((4-(trifluoromethyl)-1,3-thiazol-2-yl)methoxy)pyridin-2(1H)-one

A mixture of 4-(benzyloxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyrazin-6-yl)pyridin-2(1H)-one (113 mg), 10% Pd/C (32.3 mg) and MeOH (5 ml) was stirred under H 2 atmosphere at room temperature for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The resulting residue was dissolved in THF (2 ml), to which (4-(trifluoromethyl)-1,3-thiazol-2-yl)methanol (67.0 mg), bis(2-methoxyethyl) azodicarboxylate (93 mg) and triphenylphosphine (104 mg) were added, and the resulting mixture was stirred at room temperature for 3 h. The mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO 4 , concentrated in vacuo, and purified by silica gel column chromatography (EtOAc/MeOH), followed by crystallization from hot EtOAc-hexane to give the title compound (35.3 mg) as white crystals.

MS (ESI+): [M+H]+ 448.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.91-1.05 (4H, m), 2.19 (1H, d, J=4.6 Hz), 2.55 (3H, s), 5.58 (2H, s), 6.12 (1H, brs), 6.24 (1H, d, J=6.9 Hz), 7.83 (1H, d, J=7.7 Hz), 8.62 (1H, s), 8.71 (1H, s), 8.83 (1H, s).

4-((5-Chloro-1,2,4-thiadiazol-3-yl)methoxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 190 using 5-chloro-3-(chloromethyl)-1,2,4-thiadiazole and 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one.

MS (ESI+): [M+H]+ 414.3.

Reference Example 197

4-((4-Chlorobenzyl)oxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-b]pyridazin-6-yl)pyridin-2(1H)-one

A) 6-Bromo-2-cyclopropyl-3-methylimidazo[1,2-b]pyridazine

To a solution of 6-bromopyridazin-3-amine (1.0 g) in DMA (10 ml) were added 2-bromo-1-cyclopropylpropan-1-one (2.04 g) and NaHCO 3 (0.966 g) at room temperature, and the mixture was stirred at 80° C. for 16 h. The mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO 4 , concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.10 g) as yellow crystals.

MS (ESI+): [M+H]+ 252.0.

B) 4-((4-Chlorobenzyl)oxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-b]pyridazin-6-yl)pyridin-2(1H)-one

A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (108 mg), 6-bromo-2-cyclopropyl-3-methylimidazo[1,2-b]pyridazine (150 mg), N,N′-dimethyl-1,2-ethanediamine (81 mg), CuI (87 mg), potassium carbonate (190 mg) and DMSO (3 ml) was heated at 150° C. for 1 h under microwave irradiation. The mixture was poured into 28% NH 3 solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , concentrated in vacuo, and purified by column chromatography (hexane/EtOAc), followed by crystalization from EtOAc-hexane to give the title compound (52.3 mg) as pale yellow crystals.

MS (ESI+): [M+H]+ 407.3.

Reference Example 198

1-(2-Cyclopropyl-3-methylimidazo[1,2-b]pyridazin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step B in reference example 197 using 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 6-bromo-2-cyclopropyl-3-methylimidazo[1,2-b]pyridazine.

MS (ESI+): [M+H]+ 391.3.

Reference Example 199

4-((4-Chlorobenzyl)oxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyrimidin-6-yl)pyridin-2(1H)-one

A) 6-Bromo-2-cyclopropyl-3-methylimidazo[1,2-a]pyrimidine

To a solution of 5-bromopyrimidin-2-amine (500 mg) in DMF (10 ml) was added 2-bromo-1-cyclopropylpropan-1-one (1.02 g) at room temperature, and the mixture was stirred at 100° C. for 24 h. The mixture was partitioned between EtOAc and 1 M NaOH, and the organic layer was washed with 1 M NaOH and brine successively, dried over MgSO 4 , concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (89 mg) as yellow crystals.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.84-1.02 (4H, m), 2.04-2.15 (1H, m), 2.50 (3H, brs), 8.41 (1H, s), 8.98 (1H, s).

B) 4-((4-Chlorobenzyl)oxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyrimidin-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step B in reference example 197 using 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one and 6-bromo-2-cyclopropyl-3-methylimidazo[1,2-a]pyrimidine.

MS (ESI+): [M+H]+ 407.4.

1-(2-(2,4-Dimethyl-1,3-oxazol-5-yl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 2,4-dimethyl-1,3-oxazole-5-carboxylic acid.

MS (ESI+): [M+H]+ 445.4.

1-(2-(4-Ethyl-1,3-oxazol-5-yl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (67.9 mg), 4-ethyl-1,3-oxazole-5-carboxylic acid (28.2 mg), HATU (80.0 mg), N,N-diisopropylethylamine (0.105 ml) and DMF (2.0 ml) was stirred at room temperature for 2 h. The mixture was poured into saturated NaHCO 3 solution and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated in vacuo. The residue was dissolved in AcOH (1.5 ml), and the mixture was stirred at 80° C. for 1 h. The mixture was concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOAc-hexane to give the title compound (15.7 mg) as a white solid.

MS (ESI+): [M+H]+ 445.4.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.25 (3H, t, J=7.3 Hz), 2.95-3.03 (2H, m), 4.00 (3H, s), 5.15 (2H, s), 6.02 (1H, s), 6.12 (1H, d, J=9.7 Hz), 7.21 (1H, d, J=8.5 Hz), 7.26 (2H, t, J=8.7 Hz), 7.49-7.59 (2H, m), 7.63 (1H, d, J=7.5 Hz), 7.70-7.80 (2H, m), 8.60 (1H, s).

4-((5-Chloro-2-furyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a mixture of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (5-chloro-2-furyl)methanol (94 mg), tributylphosphine (0.264 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc), followed by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (3.8 mg) as an off-white solid.

MS (ESI+): [M+H]+396.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.01-1.13 (4H, m), 2.23-2.30 (1H, m), 3.85 (3H, s), 5.10 (2H, s), 6.04-6.10 (2H, m), 6.53 (1H, d, J=3.3 Hz), 6.78 (1H, d, J=3.0 Hz), 7.05 (1H, d, J=9.0 Hz), 7.49-7.55 (2H, m), 7.58 (1H, d, J=8.3 Hz).

4-((5-Chloro-2-thienyl)methoxy)-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) 4-Hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 4-(benzyloxy)-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (1.35 g), 10% Pd/C (0.6 g) and MeOH (30 ml) was stirred under H 2 atmosphere at room temperature for 3 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound (950 mg) as an off-white solid.

MS (ESI+): [M+H]+ 340.3.

B) 4-((5-Chloro-2-thienyl)methoxy)-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (5-chloro-2-thienyl)methanol (88 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (EtOAc/MeOH), followed by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from IPE-IPA to give the title compound (29.1 mg) as an off-white solid.

MS (ESI+): [M+H]+ 470.1.

1 H NMR (300 MHz, DMSO-d 6 ): δ 1.06-1.13 (6H, m), 1.27 (1H, td, J=4.1, 8.9 Hz), 1.36-1.44 (1H, m), 1.56-1.66 (1H, m), 2.27 (1H, td, J=6.3, 8.8 Hz), 3.87 (3H, s), 5.30 (2H, s), 5.86 (1H, s), 6.03-6.09 (2H, m), 7.05-7.13 (2H, m), 7.17 (1H, d, J=3.8 Hz), 7.51-7.65 (3H, m).

4-((5-Chloropyridin-2-yl)methoxy)-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (5-chloropyridin-2-yl)methanol (85 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, quenched with water, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , filtered through silica pad, and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by recrystallization from IPA-IPE to give the title compound (68.4 mg) as an off-white solid.

MS (ESI+): [M+H]+ 465.4.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.09 (6H, s), 1.27 (1H, td, J=4.0, 8.8 Hz), 1.36-1.44 (1H, m), 1.61 (1H, q, J=8.2 Hz), 2.23-2.31 (1H, m), 3.86 (3H, s), 5.24 (2H, s), 5.86 (1H, s), 5.97 (1H, s), 6.14 (1H, d, J=7.5 Hz), 7.09 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=8.5 Hz), 7.58 (1H, s), 7.59-7.65 (2H, m), 8.03 (1H, d, J=8.3 Hz), 8.67 (1H, s).

4-((4-Fluorobenzyl)oxy)-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (4-fluorophenyl)methanol (74.3 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO 4 , filtered through NH silica gel pad, and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was washed with toluene, and recrystallized from IPA-IPE to give the title compound (49.6 mg) as an off-white solid.

MS (ESI+): [M+H]+ 448.2.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.09 (6H, s), 1.23-1.32 (1H, m), 1.36-1.44 (1H, m), 1.56-1.65 (1H, m), 2.23-2.31 (1H, m), 3.87 (3H, s), 5.14 (2H, s), 5.86 (1H, s), 5.99 (1H, d, J=2.1 Hz), 6.09 (1H, dd, J=1.8, 7.6 Hz), 7.09 (1H, d, J=8.4 Hz), 7.21-7.31 (2H, m), 7.49-7.58 (4H, m), 7.61 (1H, d, J=7.7 Hz).

4-((4-Chlorobenzyl)oxy)-1-(2-((1RS,2SR)-2-(3-hydroxypentan-3-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

Ethylmagnesium bromide (1.0 M solution in THF, 1.29 ml) was added to a solution of methyl(1RS,2RS)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate (150 mg) in THF (5 ml) at 0° C., and the mixture was stirred at room temperature for 3 h. The mixture was quenched with saturated NH 4 Cl solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (EtOAc/MeOH), and the resulting solid was crystallized from EtOH to give the title compound (48 mg) as a white solid.

MS (ESI+): [M+H]+ 493.5.

1 H NMR (400 MHz, CDCl 3 ): δ 0.85 (3H, t, J=7.4 Hz), 1.01 (3H, t, J=7.4 Hz), 1.31-1.45 (2H, m), 1.46-1.54 (1H, m), 1.60-1.75 (4H, m), 1.92-2.06 (1H, m), 3.82 (3H, s), 5.03 (2H, s), 5.99-6.07 (2H, m), 6.64 (1H, s), 7.10 (1H, d, J=8.5 Hz), 7.27-7.33 (1H, m), 7.33-7.42 (5H, m), 7.62 (1H, d, J=8.5 Hz).

4-((4-Chlorobenzyl)oxy)-1-(2-((1R*,2S*)-2-(2-fluoropropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (optically active, IA tR2)

BAST (0.294 ml) was added to a solution of 4-((4-chlorobenzyl)oxy)-1-(2-((1R*,2S*)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (optically active, AYH tR2, 185 mg) obtained in Example 154 in toluene (3 ml) at 0° C., and the mixture was stirred for 30 min. The resulting mixture was quenched with saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/MeOH) to give the title compound (87 mg) as a white solid.

MS (ESI+): [M+H]+ 466.4.

1 H NMR (400 MHz, CDCl 3 ): δ 0.92 (3H, d, J=21.3 Hz), 1.35-1.49 (4H, m), 1.68-1.82 (2H, m), 2.12-2.22 (1H, m), 3.84 (3H, s), 5.03 (2H, s), 6.01-6.10 (2H, m), 7.13 (1H, d, J=8.3 Hz), 7.31 (1H, d, J=7.3 Hz), 7.33-7.42 (5H, m), 7.75 (1H, d, J=8.5 Hz).

Analysis of enantiomeric excess

Column: CHIRALPAK IA (4.6×250 mm)

Mobile phase: Hexane/EtOH=3/7 (v/v/v)

Flow rate: 0.5 ml/min

Temperature: 30° C.

Detection: UV: 220 nm

Retention time: 23.75 min

4-((4-Chlorobenzyl)oxy)-1-(1-methyl-2-propanoyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) 1-(6-Bromo-1-methyl-1H-benzimidazol-2-yl)propan-1-one

Ethylmagnesium bromide (1 M in THF, 11.0 ml) was added to a solution of 6-bromo-N-methoxy-N,1-dimethyl-1H-benzo[d]imidazole-2-carboxamide (1.09 g) in THF (15 ml) at 0° C. The mixture was stirred at 0° C. under N 2 atmosphere for 2 h. The mixture was quenched with saturated NH 4 Cl solution, and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc) to give the title compound (0.86 g) as a white solid.

MS (ESI+): [M+H]+ 267.0.

B) 4-((4-Chlorobenzyl)oxy)-1-(1-methyl-2-propanoyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (100 mg), 1-(6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)propan-1-one (170 mg), N,N′-dimethylethylenediamine (0.046 ml), CuI (81 mg) and potassium carbonate (176 mg) in DMSO (3 ml) was stirred at 150° C. for 30 min under N 2 atmosphere. The mixture was purified by NH silica gel column chromatography (hexane/EtOAc), followed by recrystallization from IPA to give the title compound (6.1 mg) as a pale yellow solid.

MS (ESI+): [M+H]+ 422.1.

1 H NMR (400 MHz, CDCl 3 ): δ 1.27 (3 H, t, J=7.3 Hz), 3.35 (2 H, q, J=7.2 Hz), 4.13 (3 H, s), 5.03 (2 H, s), 6.03-6.12 (2 H, m), 7.30 (2 H, t, J=7.6 Hz), 7.34-7.42 (4 H, m), 7.50 (1 H, s), 7.96 (1 H, d, J=8.5 Hz).

4-((4-Chlorobenzyl)oxy)-1-(2-((1R*,2S*)-2-(2-fluoropropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (optically active, IA tR1)

BAST (0.296 ml) was added to a solution of 4-((4-chlorobenzyl)oxy)-1-(2-((1R*,2S*)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (optically active, AYH tR1, 186 mg) obtained in Example 153 in toluene (3 ml) at 0° C., and the mixture was stirred for 30 min. The mixture was quenched with saturated NaHCO 3 solution at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/MeOH) to give the title compound (15 mg) as an off-white solid.

MS (ESI+): [M+H]+ 466.4.

1 H NMR (400 MHz, CDCl 3 ): δ 0.92 (3H, d, J=21.8 Hz), 1.35-1.44 (4H, m), 1.67-1.82 (2H, m), 2.13-2.23 (1H, m), 3.84 (3H, s), 5.03 (2H, s), 6.02-6.09 (2H, m), 7.13 (1H, d, J=8.5 Hz), 7.31 (1H, d, J=7.3 Hz), 7.33-7.42 (5H, m), 7.75 (1H, d, J=8.5 Hz).

Analysis of enantiomeric excess

Column: CHIRALPAK IA (4.6×250 mm)

Mobile phase: Hexane/EtOH=3/7 (v/v)

Flow rate: 0.5 ml/min

Temperature: 30° C.

Detection: UV: 220 nm

Retention time: 18.89 min

4-(Benzyloxy)-1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 4-(benzyloxy)pyridin-2(1H)-one (1.0 g), 6-bromo-2-ethyl-1-methyl-1H-benzimidazole (1.19 g), potassium carbonate (2.06 g), N,N′-dimethylethylenediamine (0.53 ml), CuI (0.95 g) and DMSO (20 ml) was stirred at 150° C. for 2 h. After cooling to 0° C., 28% NH 3 solution (56.0 ml) was added. The precipitate was collected by filtration. The collected material was dissolved in THF, passed through a plug of NH silica gel (EtOAc) and concentrated in vacuo. The resulting solid was collected to give the title compound (1.03 g) as a pink solid.

MS (ESI+): [M+H]+ 360.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.33 (3H, t, J=7.4 Hz), 2.90 (2H, q, J=7.5 Hz), 3.74 (3H, s), 5.16 (2H, s), 5.98 (1H, s), 6.10 (1H, d, J=5.4 Hz), 7.07 (1H, d, J=8.8 Hz), 7.34-7.51 (5H, m), 7.53 (1H, s), 7.55-7.62 (2H, m).

4-((5-Chlorothiophen-2-yl)methoxy)-1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chloro-2-thienyl) methanol (166 mg) and tributylphosphine (388 mg) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (422 mg), and the reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (16.1 mg) as a white solid.

MS (ESI+): [M+H]+ 400.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.33 (3H, t, J=7.5 Hz), 2.90 (2H, q, J=7.7 Hz), 3.74 (3H, s), 5.30 (2H, s), 6.00-6.11 (2H, m), 7.09 (2H, d, J=4.0 Hz), 7.17 (1H, d, J=3.5 Hz), 7.53 (1H, s), 7.58 (1H, s), 7.60 (1H, d, J=2.8 Hz).

4-((3,4-Difluorobenzyl)oxy)-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (3,4-difluorophenyl)methanol (0.066 ml), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, and quenched with water. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , filtered through NH silica gel pad, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from IPA-IPE to give the title compound (51.4 mg) as an off-white solid.

MS (ESI+): [M+H]+ 466.4.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.09 (6H, s), 1.23-1.32 (1H, m), 1.36-1.44 (1H, m), 1.57-1.66 (1H, m), 2.23-2.31 (1H, m), 3.87 (3H, s), 5.14 (2H, s), 5.86 (1H, s), 5.99 (1H, d, J=2.1 Hz), 6.11 (1H, dd, J=2.3, 7.7 Hz), 7.09 (1H, d, J=7.5 Hz), 7.31-7.38 (1H, m), 7.44-7.67 (5H, m).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-methyl-3-thienyl)methoxy)pyridin-2(1H)-one

A) tert-Butyl(dimethyl)(3-thienylmethoxy)silane

A mixture of tert-butyldimethylchlorosilane (1.58 g), triethylamine (2.44 ml), 3-thiophenemethanol (0.822 ml) and DMF (20 ml) was stirred at 60° C. for 1 h. Additional DMF (20 ml) was added to the reaction mixture, and the mixture was stirred at 60° C. for 2 h. The mixture was quenched with saturated NaHCO 3 solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane) to give the title compound (1.6 g) as a colorless oil.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.00 (6H, s), 0.83 (9H, s), 4.62 (2H, s), 6.95-7.00 (1H, m), 7.22-7.28 (1H, m), 7.41-7.46 (1H, m).

B) (5-Methyl-3-thienyl)methanol

To a solution of tert-butyl(dimethyl)(3-thieylmethoxy)silane (150 mg) in THF (1 ml) was added sec-butyllithium (1 M in cyclohexane/n-hexane, 0.79 ml) at −78° C., and the mixture was stirred for 30 min. Iodomethane (0.049 ml) was added, and the mixture was stirred at the same temperature for 1 h, and then raised to room temperature slowly. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , and concentrated in vacuo. The resulting residue was dissolved in THF (1 ml), and TBAF (1 M in THF, 0.79 ml) was added to the solution. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , filtered through NH silica gel pad and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (72 mg) as a mixture with (2-methyl-3-thienyl) ethanol.

1 H NMR (400 MHz, CDCl 3 ): δ 1.59 (1H, brs), 2.47 (3H, s), 4.59 (2H, brs), 6.75 (1H, s), 6.96 (1H, s).

C) 1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-methyl-3-thienyl)methoxy)pyridin-2(1H)-one

A mixture of (5-methyl-3-thienyl)methanol (72 mg), 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), tributylphosphine (0.264 ml), 1,1′-(azodicarbonyl)dipiperidine (269 mg) and THF (10 ml) was stirred at 60° C. for 3 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried with MgSO 4 , and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc) to give the title compound as a mixture with 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((2-methyl-3-thienyl)methoxy)pyridin-2(1H)-one. This mixture was subjected to HPLC separation (C18, mobile phase: H 2 O/CH 3 CN (0.1% TFA included)). The solution was neutralized with saturated Na 2 CO 3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , filtered through a plug of silica gel and concentrated in vacuo. The resulting solid was recrystallized from EtOH to give the title compound (15.8 mg) as an off-white solid.

MS (ESI+): [M+H]+ 392.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.00-1.14 (4H, m), 2.22-2.31 (1H, m), 2.45 (3H, s), 3.85 (3H, s), 5.04 (2H, s), 5.98 (1H, d, J=2.6 Hz), 6.05 (1H, dd, J=2.3, 7.5 Hz), 6.88 (1H, s), 7.02-7.07 (1H, m), 7.36 (1H, s), 7.48-7.59 (3H, m).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((2-methyl-3-thienyl)methoxy)pyridin-2(1H)-one

A) (2-Methyl-3-thienyl)methanol

The title compound was obtained in step B in example 213 as a mixture with (5-methyl-3-thienyl)methanol.

1 H NMR (400 MHz, CDCl 3 ): δ 1.67 (1H, brs), 2.46 (3H, s), 4.60 (2H, brs), 6.97-7.01 (1H, m), 7.03-7.06 (1H, m).

B) 1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((2-methyl-3-thienyl)methoxy)pyridin-2(1H)-one

A mixture of the title compound and 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-methyl-3-thienyl)methoxy)pyridin-2(1H)-one obtained in step C in example 213 was subjected to HPLC separation (C18, mobile phase: H 2 O/CH 3 CN (0.1% TFA included)). The solution was neutralized with saturated Na 2 CO 3 and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , filtered through a plug of silica gel, and concentrated in vacuo. The residue was recrystallized from EtOH to give the title compound (4.3 mg) as an off-white solid.

MS (ESI+): [M+H]+ 392.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.00-1.13 (4H, m), 2.22-2.31 (1H, m), 2.45 (3H, s), 3.85 (3H, s), 5.05 (2H, s), 6.02 (1H, d, J=2.3 Hz), 6.05 (1H, dd, J=2.4, 7.5 Hz), 7.01-7.09 (2H, m), 7.30 (1H, d, J=5.1 Hz), 7.49-7.59 (3H, m).

4-((5-Chloro-3-thienyl)methoxy)-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (5-chloro-3-thienyl)methanol (77 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The solvent was evaporated, and the residue was purified by column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was suspended in toluene, and the insoluble material was collected by filtration to give the title compound (12 mg) as an off-white solid.

MS (ESI+): [M+H]+ 470.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.06-1.12 (6H, m), 1.23-1.31 (1H, m), 1.37-1.44 (1H, m), 1.57-1.66 (1H, m), 2.23-2.31 (1H, m), 3.87 (3H, s), 5.06 (2H, s), 5.86 (1H, s), 5.99 (1H, d, J=2.3 Hz), 6.08 (1H, dd, J=2.4, 7.5 Hz), 7.09 (1H, d, J=8.5 Hz), 7.21 (1H, s), 7.50-7.66 (4H, m).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one

A) (5-Fluoro-3-thienyl)methanol

To a solution of tert-butyl(dimethyl) (3-thienylmethoxy)silane (300 mg) in THF (3 ml) was added sec-butyllithium (1 M in cyclohexane/n-hexane, 1.58 ml) at −78° C., and the mixture was stirred for 30 min. NFSI (497 mg) was added to the mixture, and the resulting mixture was stirred at the same temperature for 1 h and allowed to warm to room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , and concentrated in vacuo. The residue was dissolved with THF (3 ml), and TBAF (1 M in THF, 1.58 ml) was added to the solution. The mixture was stirred at room temperature for 3 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (130 mg) as a mixture with (2-fluoro-3-thienyl)methanol.

1 H NMR (400 MHz, CDCl 3 ): δ 4.55 (2H, s), 6.48 (1H, s), 6.55 (1H, brs).

B) 1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one

A mixture of (5-fluoro-3-thienyl)methanol (130 mg), 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), tributylphosphine (0.264 ml), 1,1′-(azodicarbonyl)dipiperidine (269 mg) and THF (10 ml) was stirred at 60° C. for 3 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried with MgSO 4 , filtered and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (EOAc/MeOH), followed by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound as a mixture with 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((2-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one. This mixture was subjected to HPLC separation (C18, mobile phase: H 2 O/CH 3 CN (0.1% TFA included)). The solution was neutralized with saturated Na 2 CO 3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , filtered through a plug of silica gel and concentrated in vacuo. The resulting solid was recrystallized from EtOH to give the title compound (18.1 mg) as an off-white solid.

MS (ESI+): [M+H]+ 396.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.00-1.13 (4H, m), 2.22-2.30 (1H, m), 3.85 (3H, s), 5.01 (2H, s), 5.95-6.02 (1H, m), 6.07 (1H, dd, J=7.7, 2.3 Hz), 6.82 (1H, s), 7.04 (1H, d, J=9.0 Hz), 7.11 (1H, brs), 7.48-7.63 (3H, m).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((2-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one

A) (2-Fluoro-3-thienyl)methanol

The title compound was obtained in step A in example 216 as a mixture with (5-fluoro-3-thienyl)methanol.

1 H NMR (400 MHz, CDCl 3 ): δ 4.61 (2H, s), 6.60-6.67 (1H, m), 6.80 (1H, dd, J=3.7, 6.0 Hz).

B) 1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((2-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one

A mixture of the title compound and 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one obtained in step B in example 216 was subjected to HPLC separation (C18, mobile phase: H 2 O/CH 3 CN (0.1% TFA included)). The solution was neutralized with saturated Na 2 CO 3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , filtered through a plug of silica gel, and concentrated in vacuo. The residue was recrystallized from EtOH to give the title compound (12.8 mg) as an off-white solid.

MS (ESI+): [M+H]+ 396.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.01-1.13 (4H, m), 2.23-2.31 (1H, m), 3.85 (3H, s), 5.04 (2H, s), 6.02 (1H, d, J=1.9 Hz), 6.05 (1H, dd, J=2.2, 7.2 Hz), 6.96 (1H, dd, J=3.4, 5.9 Hz), 7.02-7.08 (2H, m), 7.48-7.61 (3H, m).

3-(6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarbonitrile (Retention time: short)

A) N-(2-Amino-4-bromophenyl)-3-oxocyclobutanecarboxamide

To a stirred solution of 3-oxocyclobutanecarboxylic acid (1.1 g) in DMF (50 ml) were added HATU (5.7 g) and N,N-diisopropylethylamine (4.2 ml) at 0° C., and the mixture was allowed to warm to room temperature for 30 min. A solution of 4-bromo-N 2 -methylbenzene-1,2-diamine (2.0 g) in DMF (2 ml) was added, and the resulting mixture was stirred at room temperature for 18 h. The mixture was concentrated in vacuo and diluted with DCM. The mixture was washed with saturated NH 4 Cl solution, saturated NaHCO 3 solution and brine successively, dried over Na 2 SO 4 , concentrated in vacuo and purified by column chromatography (hexane/EtOAc) to afford the title compound (2.7 g) as an off-white solid.

MS (ESI+): [M+H]+ 297.2.

B) 3-(6-Bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutanone

To a stirred solution of N-(2-amino-4-bromophenyl)-3-oxocyclobutanecarboxamide (2.7 g) in CH 3 CN (20 ml) was added AcOH (2 ml), and the mixture was heated under reflux for 3 h. The mixture was concentrated in vacuo, and poured into saturated NaHCO 3 solution. The mixture was extracted with EtOAc, washed with water and brine successively, dried over Na 2 SO 4 , concentrated in vacuo, and purified by column chromatography (hexane/EtOAc) to afford the title compound (2.0 g) as an off-white solid.

MS (ESI+): [M+H]+ 281.2.

C) 6-Bromo-2-(3-(methoxymethylidene)cyclobutyl)-1H-benzimidazole

To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (4.98 g) in THF (20 ml) was added lithium hexamethyldisilazide (1.0 M solution in hexane, 29 ml) at −15° C., and the resulting mixture was stirred at the same temperature for 30 min. A solution of 3-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutanone (2.7 g) in THF (5 ml) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NH 4 Cl solution, concentrated in vacuo and diluted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , concentrated in vacuo and purified by column chromatography (hexane/EtOAc) to afford the title compound (850 mg) as a yellow solid.

MS (ESI+): [M+H]+ 307.0.

D) 3-(6-Bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarbaldehyde

To a solution of 6-bromo-2-(3-(methoxymethylidene)cyclobutyl)-1H-benzimidazole (850 mg) in CH 3 CN (20 ml) was added 2 M HCl (4.2 ml), and the resulting mixture was stirred at same temperature for 16 h. The reaction mixture was then quenched with saturated NaHCO 3 solution, and extracted with DCM. The extract was washed with brine, dried over Na 2 SO 4 , concentrated in vacuo and purified by column chromatography (hexane/EtOAc) to afford two isomers of the title compound (Less polar isomer: 200 mg, polar isomer: 300 mg) as yellow sticky solids.

Data for less polar isomer: 1 H NMR (400 MHz, DMSO-d 6 ): δ 2.31-2.48 (2H, m), 2.57-2.71 (3H, m), 3.62-3.63 (3H, m), 3.77-3.81(1H, m), 7.29 (1H, dd, J=1.5, 8.2 Hz), 7.54 (1H, d, J=8.4Hz), 7.79 (1H, d, J=1.6 Hz), 9.84 (1H, s).

Data for polar isomer: 1 H NMR (400 MHz, DMSO-d 6 ): δ 2.31-2.34(1H, m), 2.56-2.60 (4H, m), 3.62-3.63 (4H, m), 7.27 (1H, dd, J=1.5, 8.3 Hz), 7.52 (1H, d, J=8.4 Hz), 7.76 (1H, d, J=1.1 Hz), 9.66 (1H, d, J=1.2 Hz).

E) 1-(3-(6-Bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutyl)-N-hydroxymethanimine (Retention time: short)

To a stirred solution of 3-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarbaldehyde (less polar isomer, 200 mg) in EtOH (10 ml) was added hydroxylamine hydrochloride (50 mg), and the resulting mixture was heated under reflux for 2 h. The reaction mixture was concentrated in vacuo to afford the title compound (200 mg) as an off-white solid.

LC/MS Analysis

Column: Zorbax Extend C18 (4.6×50 mm)

Mobile Phase:

10 mM NH 4 OAc in H 2 O/CH 3 CN=9/1 to 7/3 (v/v) from 0 to 1.5 min

10 mM NH 4 OAc in H 2 O/CH 3 CN=7/3 to 1/9 (v/v) from 1.5 to 3.0 min

10 mM NH 4 OAc in H 2 O/CH 3 CN=1/9 (v/v) from 3.0 to 4.0 min

Detection: UV: 220 nm

Retention time: 2.82 min

MS (ESI+): [M+H]+ 308.0.

F) 3-(6-Bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarbonitrile (Retention time: short)

To a stirred solution of 1-(3-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutyl)-N-hydroxymethanimine (100 mg) in CH 3 CN (10 ml) was added phosphorous oxychloride (1 ml), and the mixture was stirred at room temperature for 16 h. The mixture was then concentrated in vacuo and poured into saturated NaHCO 3 solution. The mixture was extracted with DCM, and the organic layer was washed with brine, dried over Na 2 SO 4 and purified by column chromatography (MeOH/DCM) to afford the title compound (50 mg) as a yellow solid.

LC/MS Analysis

Column: Zorbax Extend C18 (4.6×50 mm)

Mobile Phase:

10 mM NH 4 OAc in H 2 O/CH 3 CN=9/1 to 7/3 (v/v) from 0 to 1.5 min

10 mM NH 4 OAc in H 2 O/CH 3 CN=7/3 to 1/9 (v/v) from 1.5 to 3.0 min

10 mM NH 4 OAc in H 2 O/CH 3 CN=1/9 (v/v) from 3.0 to 4.0 min

Detection: UV: 220 nm

Retention time: 2.94 min

MS (ESI+): [M+H]+ 290.0.

G) 3-(6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarbonitrile (Retention time: short)

The title compound was obtained in an analogous manner to step C in example 5 using 3-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarbonitrile and 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one.

MS (ESI+): [M+H]+ 429.2.

HPLC analysis (C18, mobile phase: H 2 O/CH 3 CN (0.05% TFA included))

Column: Zorbax SB C18 (4.6×50 mm)

Mobile Phase:

0.05% TFA in H 2 O/CH 3 CN=98/2 to 75/25 (v/v) from 0 to 0.5 min

0.05% TFA in H 2 O/CH 3 CN=75/25 to 65/35 (v/v) from 0.5 to 6.5 min

0.05% TFA in H 2 O/CH 3 CN=65/35 to 10/90 (v/v) from 6.5 to 8.0 min

0.05% TFA in H 2 O/CH 3 CN=10/90 (v/v) from 8.0 to 13.0 min

Detection: UV: 220 nm

Flow rate: 1 mL/min

Retention time: 5.488 min

4-((4-Fluorobenzyl)oxy)-1-(1-methyl-2-(1-methyl-1H-pyrazol-5-yl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 13 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one and 1-methyl-1H-pyrazole-5-carboxylic acid.

MS (ESI+): [M+H]+ 430.4.

4-((4-Chloro-3-fluorobenzyl)oxy)-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (4-chloro-3-fluorophenyl)methanol (0.073 ml), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. overnight. The solvent was evaporated, and the residue was purified by column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from IPA-EtOAc to give the title compound (59.7 mg) as an off-white solid.

MS (ESI+): [M+H]+ 482.2.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.09 (6H, s), 1.23-1.32 (1H, m), 1.36-1.44 (1H, m), 1.56-1.66 (1H, m), 1.64-1.64 (1H, m), 2.22-2.31 (1H, m), 3.86 (3H, s), 5.18 (2H, s), 5.86 (1H, s), 5.98 (1H, d, J=2.3 Hz), 6.13 (1H, dd, J=2.3 7.8 Hz), 7.09 (1H, d, J=8.4 Hz), 7.35 (1H, d, J=7.9 Hz), 7.51-7.59 (3H, m), 7.60-7.70 (2H, m).

4-((2-Chloro-3-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) (2-Chloro-3-thienyl)methanol

To a solution of methyl 2-chlorothiophene-3-carboxylate (530 mg) in MeOH (10 ml) was added NaBH 4 (113 mg) at room temperature, and the mixture was stirred at 60° C. for 1 day. After MeOH was evaporated, the mixture was quenched with saturated NaHCO 3 solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , filtered through a plug of silica gel, and concentrated in vacuo. The resulting residue was dissolved with THF (9 ml), where NaBH 4 (113 mg) and MeOH (1 ml) were added, and the mixture was stirred at 60° C. for 3 h. Additional NaBH 4 (113 mg) and MeOH (1 ml) were added, and the mixture was stirred at 60° C. for further 3 h. The mixture was quenched with saturated NH 4 Cl solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , filtered through a plug of silica gel, and concentrated in vacuo to give the title compound (400 mg) as a pale yellow oil.

1 H NMR (400 MHz, DMSO-d 6 ): δ 4.40 (2H, d, J=5.5 Hz), 5.21 (1H, t, J=5.6 Hz), 7.05 (1H, d, J=5.6 Hz), 7.40 (1H, d, J=5.6 Hz).

B) 4-((2-Chloro-3-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a mixture of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (2-chloro-3-thienyl)methanol (106 mg) and tributylphosphine (0.264 ml) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc), followed by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (42.4 mg) as an off-white solid.

MS (ESI+): [M+H]+ 412.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.01-1.13 (4H, m), 2.22-2.31 (1B, m), 3.85 (3H, s), 5.06 (2H, s), 6.02 (1H, d, J=2.3 Hz), 6.07 (1H, dd, J=2.5, 7.5 Hz), 7.05 (1H, dd, J=1.6, 8.5 Hz), 7.19 (1H, d, J=5.8 Hz), 7.49-7.55 (3H, m), 7.58 (1H, d, J=7.5 Hz).

4-((3-Chloro-4-fluorobenzyl)oxy)-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (3-chloro-4-fluorophenyl)methanol (95 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO 4 , filtered through a plug of NH silica gel, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc). Then the resulting solid was recrystallized from IPA-EtOAc to give the title compound (58.4 mg) as an off-white solid.

MS (ESI+): [M+H]+ 482.2.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.09 (6H, s), 1.23-1.32 (1H, m), 1.36-1.44 (1H, m), 1.56-1.66 (1H, m), 2.22-2.31 (1H, m), 3.86 (3H, s), 5.18 (2H, s), 5.86 (1H, s), 5.98 (1H, d, J=2.3 Hz), 6.13 (1H, dd, J=2.3, 7.8 Hz), 7.09 (1H, d, J=8.4 Hz), 7.35 (1H, d, J=7.9 Hz), 7.51-7.59 (3H, m), 7.60-7.70 (2H, m).

4-((4-Chlorobenzyl)oxy)-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclobutyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) (1RS,2SR)-2-(Methoxycarbonyl)cyclobutanecarboxylic acid

A mixture of 3-oxabicyclo[3.2.0]heptane-2,4-dione (1 g), triethylamine (1.36 ml) and MeOH (20 ml) was stirred at room temperature over weekend. The mixture was quenched with 1 M HCl, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , and concentrated in vacuo to give the title compound (1.18 g) as a colorless oil.

1 H NMR (400 MHz, CDCl 3 ): δ 2.17-2.31 (2H, m), 2.31-2.46 (2H, m), 3.44 (2H, t, J=7.3 Hz), 3.64-3.73 (3H, m).

B) Methyl(1RS,2SR)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarboxylate

A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (830 mg), (1RS, 2SR)-2-(methoxycarbonyl)cyclobutanecarboxylic acid (406 mg), HATU (1.33 g), N,N-diisopropylethylamine (0.611 ml) and DMF (20 ml) was stirred at room temperature for 2 h. The mixture was quenched with water, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 and concentrated in vacuo. Then a mixture of the obtained residue and AcOH (20 ml) was stirred at 80° C. for 30 min. After concentration of the mixture, the residue was poured into saturated NaHCO 3 solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , and concentrated in vacuo. The residual solid was washed with IPE to give the title compound (172 mg) as a brown solid.

MS (ESI+): [M+H]+ 478.4.

C) 4-((4-Chlorobenzyl)oxy)-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclobutyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

Methylmagnesium bromide (1.0 M in THF, 1.42 ml) was added to a solution of methyl(1RS,2SR)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarboxylate (170 mg) in THF (5 ml) at 0° C. The mixture was stirred at room temperature for 3 h. The mixture was quenched with saturated NH 4 Cl solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/MeOH) to give the title compound (45 mg) as a white solid.

MS (ESI+): [M+H]+ 478.4.

1 H NMR (400 MHz, CDCl 3 ): δ 0.98 (3H, s), 1.14 (3H, s), 1.26 (1H, s), 2.10-2.24 (1H, m), 2.40-2.59 (2H, m), 2.80-2.93 (1H, m), 3.67 (3H, s), 3.88-3.97 (1H, m), 5.03 (2H, s), 6.01-6.09 (2H, m), 7.14 (1H, d, J=8.5 Hz), 7.27-7.33 (1H, m), 7.33-7.42 (5H, m), 7.75 (1H, d, J=8.5 Hz).

(1RS,2SR)-2-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarbonitrile

A) (1RS,2SR)-2-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarboxylic acid

The title compound was obtained in an analogous manner to step A in example 148 using 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one and 3-oxabicyclo[3.2.0]heptane-2,4-dione.

MS (ESI+): [M+H]+ 464.2.

B) (1RS,2SR)-2-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarboxamide

The title compound was obtained in an analogous manner to example 83 using (1RS,2SR)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarboxylic acid.

MS (ESI+): [M+H]+ 463.4.

C) (1RS,2SR)-2-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarbonitrile

The title compound was obtained in an analogous manner to example 86 using (1RS,2SR)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarboxamide.

MS (ESI+): [M+H]+ 445.4.

3-(6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarbonitrile (Retention time: long)

A) 1-(3-(6-Bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutyl)-N-hydroxymethanimine (Retention time: long)

The title compound was obtained in an analogous manner to step E in example 218 using 3-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarbaldehyde (polar isomer).

LC/MS Analysis

Column: Zorbax Extend C18 (4.6×50 mm)

Mobile phase:

10 mM NH 4 OAc in H 2 O/CH 3 CN=9/1 to 7/3 (v/v) from 0 to 1.5 min

10 mM NH 4 OAc in H 2 O/CH 3 CN=7/3 to 1/9 (v/v) from 1.5 to 3.0 min

10 mM NH 4 OAc in H 2 O/CH 3 CN=1/9 (v/v) from 3.0 to 4.0 min

Detection: UV: 220 nm

Retention time: 3.02 min

MS (ESI+): [M+H]+ 308.0.

B) 3-(6-Bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarbonitrile (Retention time: long)

The title compound was obtained in an analogous manner to step F in example 218 using 1-(3-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutyl)-N-hydroxymethanimine.

LC/MS Analysis

Column: Zorbax Extend C18 (4.6×50 mm)

Mobile Phase:

10 mM NH 4 OAc in H 2 O/CH 3 CN=9/1 to 7/3 (v/v) from 0 to 1.5 min

10 mM NH 4 OAc in H 2 O/CH 3 CN=7/3 to 1/9 (v/v) from 1.5 to 3.0 min

10 mM NH 4 OAc in H 2 O/CH 3 CN=1/9 (v/v) from 3.0 to 4.0 min

Detection: UV: 220 nm

Retention time: 3.18 min

MS (ESI+): [M+H]+ 290.0.

C) 3-(6-(4-((4-Fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarbonitrile (Retention time: long)

The title compound was obtained in an analogous manner to step C in example 5 using 3-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarbonitrile and 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one.

MS (ESI+): [M+H]+ 429.2.

HPLC analysis (C18, mobile phase: H 2 O/CH 3 CN (0.05% TFA included))

Column: Zorbax SB C18 (4.6×50 mm)

Mobile Phase:

0.05% TFA in H 2 O/CH 3 CN=90/10 (v/v) from 0 to 0.5 min

0.05% TFA in H 2 O/CH 3 CN=90/10 to 70/30 (v/v) from 0.5 to 3.0 min

0.05% TFA in H 2 O/CH 3 CN=70/30 to 50/50 (v/v) from 3.0 to 6.0 min

0.05% TFA in H 2 O/CH 3 CN=50/50 to 10/90 (v/v) from 6.0 to 10.0 min

0.05% TFA in H 2 O/CH 3 CN=10/90 (v/v) from 10.0 to 14.0 min

Detection: UV: 220 nm

Flow rate: 1 mL/min

Retention time: 5.634 min

4-((5-Chloro-3-thienyl)methoxy)-1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (2.5 g), (5-chloro-3-thienyl)methanol (2.48 g) and tributylphosphine (5.63 g) in THF (150 ml) was added 1,1′-(azodicarbonyl)dipiperidine (7.03 g), and the reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature. The mixture was poured into water and extracted with EtOAc. The extract was washed With brine, dried over MgSO 4 , concentrated and purified by NH silica gel column chromatography (hexane/EtOAc then ETOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (1.15 g) as a white solid.

MS (ESI+): [M+H]+ 400.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.33 (3H, t, J=7.5 Hz), 2.90 (2H, q, J=7.1 Hz), 3.74 (3H, s), 5.06 (2H, s), 5.99 (1H, s), 6.07 (1H, d, J=7.4 Hz), 7.06 (1H, d, J=10.5 Hz), 7.21 (1H, s), 7.53 (1H, s), 7.55-7.63 (3H, m).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((2,5-dichloro-3-thienyl)methoxy)pyridin-2(1H)-one

To a mixture of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (2,5-dichloro-3-thienyl)methanol (130 mg), tributylphosphine (0.264 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc), followed by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (39.9 mg) as an off-white solid.

MS (ESI+): [M+H]+ 447.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.00-1.13 (4H, m), 2.22-2.32 (1H, m), 3.85 (3H, s), 5.02 (2H, s), 6.02 (1H, d, J=2.5 Hz), 6.07 (1H, dd, J=2.6, 7.5 Hz), 7.05 (1H, dd, J=1.9, 8.5 Hz), 7.30 (1H, s), 7.52 (2H, dd, J=3.2, 5.1 Hz), 7.59 (1H, d, J=7.7 Hz).

4-((4-Chlorothiophen-2-yl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), 4-chlorothiophen-2-methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred at 60° C. for 4 h. The reaction mixture was concentrated in vacuo, and diluted with DCM. The organic layer was washed with water and brine successively, dried over Na 2 SO 4 , concentrated in vacuo and purified by column chromatography, (MeOH/DCM) to afford the title compound (53 mg) as an off-white solid.

MS (ESI+): [M+H]+ 412.2.

1 HNMR (400 MHz, DMSO-d 6 ): δ 1.04-1.09 (4H, m), 2.26 (1H, m), 3.85 (3H, s), 5.32 (2H, s), 6.03-6.08 (2H, m), 7.04 (1H, dd, J=1.8, 8.5 Hz), 7.28 (1H, s), 7.50-7.52 (2H, m), 7.58 (1H, d, J=7.5 Hz), 7.64 (1H, s).

4-((4-Chloro-3-fluorobenzyl)oxy)-1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (500 mg), (4-chloro-3-fluorophenyl)methanol (596 mg) and tributylphosphine (1.13 g) in THF (20 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.41 g), and the reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (265 mg) as a white solid.

MS (ESI+): [M+H]+ 412.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.33 (3H, t, J=7.5 Hz), 2.90 (2H, q, J=7.5 Hz), 3.74 (3H, s), 5.18 (2H, s), 5.97 (1H, d, J=2.6 Hz), 6.12 (1H, dd, J=2.4, 7.5 Hz), 7.07 (1H, d, J=8.4 Hz), 7.35 (1H, d, J=8.5 Hz), 7.52-7.57 (2H, m), 7.60 (2H, dd, J=4.8, 7.8 Hz), 7.66 (1H, t, J=8.2 Hz).

(1RS,2SR)-2-(6-(4-(Benzyloxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarbonitrile

A) (1RS,2SR)-2-(6-(4-(Benzyloxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylic acid

The title compound was obtained in an analogous manner to step A in example 148 using 1-(4-amino-3-(methylamino)phenyl)-4-(benzyloxy)pyridin-2(1H)-one and 3-oxabicyclo[3.1.0]hexane-2,4-dione.

MS (ESI+): [M+H]+ 416.2.

B) (1RS,2SR)-2-(6-(4-(Benzyloxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxamide

The title compound was obtained in an analogous manner to example 83 using (1RS,2SR)-2-(6-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylic acid.

MS (ESI+): [M+H]+ 415.4.

C) (1RS,2SR)-2-(6-(4-(Benzyloxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarbonitrile

The title compound was obtained in an analogous manner to example 86 using (1RS,2SR)-2-(6-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxamide.

MS (ESI+): [M+H]+ 397.4.

1-(2-Ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one

A) (5-Fluoro-3-thienyl)methanol

To a solution of tert-butyl(dimethyl)(3-thienylmethoxy)silane (1.0 g) in THF (10 ml) was added sec-butyllithium (1 M in cyclohexane/n-hexane, 5.25 ml) at −78° C., and the reaction mixture was stirred under N 2 atmosphere for 30 min. NFSI (1.66 g) was added to the reaction mixture at −78° C., and the reaction mixture was stirred for 1 h. Then, the reaction mixture was warmed to room temperature slowly and stirred for 1 h. The mixture was quenched with water and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , and concentrated. The residue was dissolved in THF (10 ml), and TBAF (1 M in THF, 5.25 ml) was added to the solution. The mixture was stirred at room temperature for 3 h. The mixture was quenched with water and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (460 mg) as a mixture with (2-fluoro-3-thienyl)methanol and 3-thienylmethanol.

1 H NMR (400 MHz, CDCl 3 ): δ 4.55 (2H, s), 6.49 (1H, s), 6.55 (1H, brs).

B) 1-(2-Ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one

A mixture of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (250 mg), (5-fluoro-3-thienyl)methanol (245 mg), tributylphosphine (563 mg), 1,1′-(azodicarbonyl)dipiperidine (703 mg) and THF (10 ml) was stirred at 60° C. for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound as a mixture with 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((2-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one and 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-(3-thienylmethoxy)pyridin-2(1H)-one. This mixture was subjected to HPLC separation (C18, mobile phase: H 2 O/CH 3 CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was separated, dried over MgSO 4 and concentrated in vacuo to give the title compound (16.4 mg) as a white solid.

MS (ESI+): [M+H]+ 384.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.33 (3H, t, J=7.5 Hz), 2.90 (2H, q, J=7.7 Hz), 3.74 (3H, s), 5.01 (2H, s), 5.99 (1H, s), 6.07 (1H, d, J=7.7 Hz), 6.82 (1H, s), 7.07 (1H, d, J=9.3 Hz), 7.11 (1H, brs), 7.53 (1H, s), 7.56-7.63 (2H, m).

4-((4-Bromo-5-chloro-2-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) (4-Bromo-5-chloro-2-thienyl)methanol

Sulfuryl chloride (0.6 ml) was added to a solution of ((4-bromothiophen-2-yl)methoxy)(tert-butyl)diphenylsilane (2.0 g) in CH 3 CN (20 ml) at room temperature. The mixture was stirred at room temperature overnight. The mixture was quenched with saturated sodium thiosulfate solution (40 ml) at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (182 mg) as a brown oil.

1 H NMR (400 MHz, DMSO-d 6 ): δ 4.58 (2H, s), 5.74 (1H, brs), 6.97 (1H, s).

B) 4-((4-Bromo-5-chloro-2-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

1,1-(Azodicarbonyl)dipiperidine (269 mg) was added to a solution of 1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (4-bromo-5-chloro-2-thienyl)methanol (162 mg) and tributylphosphine (0.26 ml) in THF (5 ml) at room temperature. The mixture was stirred at 60° C. for 2 h. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) and preparative HPLC (L-Column 2 ODS, eluted with H 2 O in acetonitrile containing 0.1% TFA). The desired fraction was neutralized with saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was separated, dried over MgSO 4 and concentrated in vacuo to give the title compound (12 mg) as a white solid.

MS (ESI+): [M+H]+ 491.3.

1 H NMR (400 MHz, CDCl 3 ): δ 1.13-1.21 (2H, m), 1.23-1.30 (2H, m), 1.99-2.12 (1H, m), 3.86 (3H, s), 5.11 (2H, s), 6.02-6.06 (1H, m), 6.06-6.08 (1H, m), 7.00 (1H, s), 7.08-7.14 (1H, m), 7.32-7.37 (2H, m), 7.73 (1H, d, J=8.5 Hz).

1-(2-Ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-(trifluoromethyl)-2-thienyl)methoxy)pyridin-2(1H)-one

To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (120 mg), (5-(trifluoromethyl)-2-thienyl)methanol (162 mg) and tributylphosphine (270 mg) in THF (8 ml) was added 1,1′-(azodicarbonyl)dipiperidine (337 mg), and the reaction mixture was stirred at 60° C., for 2 h. The reaction mixture was cooled to room temperature. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH to give the title compound (33.9 mg) as a white solid.

MS (ESI+): [M+H]+ 434.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.33 (3H, t, J, =7.5 Hz), 2.90 (2H, q, J=7.5 Hz), 3.74 (3H, s), 5.45 (2H, s), 6.07 (1H, s), 6.08-6.13 (1H, m), 7.07 (1H, d, J=8.5 Hz), 7.38 (1H, d, J=2.9 Hz), 7.54 (1H, s), 7.60 (2H, dd, J=6.1, 7.8 Hz), 7.69 (1H, d, J=3.0 Hz).

1-(2-Ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((2-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one

A) (2-Fluoro-3-thienyl)methanol

The title compound was obtained in step A in example 231 as a mixture with (5-fluoro-3-thienyl)methanol and 3-thienylmethanol.

1 H NMR (400 MHz, CDCl 3 ): δ 4.61 (2H, s), 6.64 (1H, dd, J=3.8, 6.0 Hz), 6.80 (1H, dd, J=3.5, 6.0 Hz).

B) 1-(2-Ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((2-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one

A mixture of the title compound, 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one and 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-(3-thienylmethoxy)pyridin-2(1H)-one obtained in step B in example 231 was subjected to HPLC separation (C18, mobile phase: H 2 O/CH 3 CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was separated, dried over MgSO 4 and concentrated in vacuo to give the title compound (1.8 mg) as a white solid.

MS (ESI+): [M+H]+ 384.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.33 (3H, t, J=7.5 Hz), 2.91 (2H, q, J=7.4 Hz), 3.74 (3H, s), 5.04 (2H, s), 6.02 (1H, s), 6.06 (1H, d, J=7.5 Hz), 6.91-6.99 (1H, m), 7.01-7.13 (2H, m), 7.54 (1H, s), 7.59 (2H, t, J=7.2 Hz).

1-(2-Ethyl-1-methyl-1H-benzimidazol-6-yl)-4-(3-thienylmethoxy)pyridin-2(1H)-one

A) 3-Thienylmethanol

The title compound was obtained in step A in example 231 as a mixture with (5-fluoro-3-thienyl)methanol and (2-fluoro-3-thienyl)methanol.

1 H NMR (400 MHz, CDCl 3 ): δ 4.71 (2H, s), 7.10 (1H, d, J=4.8

Hz), 7.24 (1H, brs), 7.32 (1H, dd, J=3.0, 4.8 Hz).

B) 1-(2-Ethyl-1-methyl-1H-benzimidazol-6-yl)-4-(3-thienylmethoxy)pyridin-2(1H)-one

A mixture of the title compound, 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one and 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((2-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one obtained in step B in example 231 was subjected to HPLC separation (C18, mobile phase: H 2 O/CH 3 CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was separated, dried over MgSO 4 and concentrated in vacuo to give the title compound (26.8 mg) as a white solid.

MS (ESI+): [M+H]+ 366.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.33 (3H, t, J=7.5 Hz), 2.90 (2H, q, J=7.7 Hz), 3.74 (3H, s), 5.14 (2H, s), 6.01 (1H, s), 6.07 (1H, dd, J=2.8, 7.7 Hz), 7.07 (1H, d, J=8.9 Hz), 7.21 (1H, d, J=4.6 Hz), 7.53 (1H, s), 7.55-7.62 (3H, m), 7.65 (1H, s).

4-((4-Chlorothiophen-2-yl)methoxy)-1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (4-chloro-thiophen-2-yl)methanol (167 mg) and tributylphosphine (338 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (422 mg), and the mixture was stirred under at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine successively, dried over Na 2 SO 4 , concentrated in vacuo, and purified by silica gel column chromatography (MeOH/DCM) to afford the title compound as a white solid.

MS (ESI+): [M+H]+ 400.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.33 (3H, t, J=7.4 Hz), 2.90 (2H, d, J=7.6 Hz), 3.73 (3H, s), 5.32 (2H, s), 6.03 (1H, d, J=2.5 Hz), 6.07 (1H, d, J=7.3 Hz), 7.06 (1H, d, J=8.6 Hz), 7.28 (1H, s), 7.53 (1H, m), 7.58-7.60 (2H, m), 7.64 (1H, s).

(1R*,2S*)-2-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarbonitrile hydrochloride (optically active, IC tR1)

(1RS,2SR)-4-((4-Chlorobenzyl)oxy)-1-(2-(2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (460 mg) was resolved by a preparative HPLC (CHIRALPAK IC, EtOH) to give a white solid (171 mg, >99% ee). To the solution of this solid in MeOH (5 ml) was added 4M HCl in EtOAc (0.12 ml). The mixture was stirred at room temperature for 30 min. After evaporation of the solvent, the residue was crystallized from IPA-IPE to give the title compound (153 mg) as an off-white solid.

MS (ESI+): [M+H]+ 431.4.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.88 (1H, td, J=5.6, 8.5 Hz), 2.33 (1H, q, J=5.9 Hz), 2.60-2.71 (1H, m), 3.12-3.27 (1H, m), 4.04 (3H, s), 5.18 (2H, s), 6.02 (1H, d, J=2.5 Hz), 6.17 (1H, dd, J=2.5, 7.5 Hz), 7.42 (1H, d, J=8.8 Hz), 7.51 (4H, s), 7.68 (1H, d, J=7.5 Hz), 7.82 (1H, d, J=8.8 Hz), 7.96 (1H, s).

Analysis of enantiomeric excess

Column: CHIRALPAK IC (4.6×250 mm)

Mobile phase: EtOH 100%

Flow rate: 0.5 ml/min

Temperature: 30° C.

Detection: UV: 220 nm

Retention time: 13.49 min

(1R*,2S*)-2-(6-(4-((4-Chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarbonitrile hydrochloride (optically active, IC tR2)

(1RS,2SR)-4-((4-Chlorobenzyl)oxy)-1-(2-(2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (460 mg) was resolved by a preparative HPLC (CHIRALPAK IC, EtOH) to give a white solid (177 mg, >99% ee). To the solution of this solid in MeOH (5 ml) was added 4 M HCl in EtOAc (0.10 ml). The mixture was stirred at room temperature for 30 min. After evaporation of the solvent, the residue was crystallized from IPA-IPE to give the title compound (73 mg) as an off-white solid.

MS (ESI+): [M+H]+ 431.4.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.88 (1H, td, J=5.6, 8.5 Hz), 2.33 (1H, q, J=5.9 Hz), 2.60-2.71 (1H, m), 3.12-3.27 (1H, m), 4.04 (3H, s), 5.18 (2H, s), 6.02 (1H, d, J=2.5 Hz), 6.17 (1H, dd, J=2.5, 7.5 Hz), 7.42 (1H, d, J=8.8 Hz), 7.51 (4H, s), 7.68 (1H, d, J=7.5 Hz), 7.82 (1H, d, J=8.8 Hz), 7.96 (1H, s).

Analysis of Enantiomeric Excess

Column: CHIRALPAK IC (4.6×250 mm)

Mobile phase: EtOH 100%

Flow rate: 0.5 ml/min

Temperature: 30° C.

Detection: UV: 220 nm

Retention time: 16.14 min

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4,5-difluoro-2-thienyl)methoxy)pyridin-2(1H)-one

A) 2-(4-Bromo-5-fluoro-2-thienyl)-1,3-dioxolane

To a solution of 2-(4,5-dibromo-2-thienyl)-1,3-dioxolane (2 g) in THF (60 ml) was added n-butyllithium (1.6 M in n-hexane, 5.18 ml) dropwise at −78° C. under N 2 atmosphere, and the mixture was stirred for 1 h. A solution of NFSI (2.61 g) in THF (20.0 ml) was added dropwise at −78° C., and the mixture was stirred at the same temperature for 1 h, and then warmed to −60° C. slowly. The mixture was quenched with saturated NH 4 Cl solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.11 g) as a mixture with 2-(4-bromo-2-thienyl)-1,3-dioxolane.

1 H NMR (400 MHz, CDCl 3 ): δ 3.94-4.16 (4H, m), 5.95 (1H, d, J=2.6 Hz), 6.79 (1H, d, J=3.4 Hz).

B) 2-(4,5-Difluoro-2-thienyl)-1,3-dioxolane

To a solution of 2-(4-bromo-5-fluoro-2-thienyl)-1,3-dioxolane (1.14 g) in THF (10 ml) was added n-butyllithium (1.6 M in hexane, 3.66 ml) dropwise at −78° C. under N 2 atmosphere, and the mixture was stirred for 1 h. A solution of NFSI (1.85 g) in THF (15 ml) was added dropwise at −78° C., and the mixture was stirred at the same temperature for 1 h, and then warmed to −60° C. slowly. The mixture was quenched with saturated NH 4 Cl solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (586 mg) as a mixture with 2-(4-bromo-2-thienyl)-1,3-dioxolane and 2-(4-bromo-5-fluoro-2-thienyl)-1,3-dioxolane.

1 H NMR (400 MHz, CDCl 3 ): δ 3.95-4.14 (4H, m), 5.93 (1H, d, J=2.9 Hz), 6.75 (1H, d, J=3.4 Hz).

C) (4,5-Difluoro-2-thienyl)methanol

A mixture of 2-(4,5-difluoro-2-thienyl)-1,3-dioxolane (586 mg), THF (10 ml) and 6 M HCl (1 ml) was stirred at ambient temperature for 1 h. The mixture was quenched with saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc). The resulting oil was dissolved in THF (10 ml), and NaBH 4 (48.5 mg) and MeOH (0.1 ml) were added to the solution at room temperature. After the mixture was stirred at room temperature for 15 min, the mixture was poured into saturated NH 4 Cl solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (190 mg) as a mixture with (4-bromo-2-thienyl)methanol and (4-bromo-5-fluoro-2-thienyl)methanol.

1 H NMR (400 MHz, CDCl 3 ): δ 4.64 (2H, dd, J=2.1, 5.8 Hz), 6.59 (1H, d, J=3.3 Hz).

D) 1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4,5-difluoro-2-thienyl)methoxy)pyridin-2(1H)-one

A mixture of (4,5-difluoro-2-thienyl)methanol (190 mg), 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (237 mg), 1,1′-(azodicarbonyl)dipiperidine (639 mg), tributylphosphine (0.632 ml) and THF (10 ml) was stirred at 60° C. for 3 h. After the solvent was removed, the residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound as a mixture with 4-((4-bromo-2-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one and 4-((4-bromo-5-fluoro-2-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one. This mixture was subjected to HPLC separation (C18, mobile phase: H 2 O/CH 3 CN (0.1% TFA included)). The solution was neutralized with saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , filtered through a plug of silica gel and concentrated in vacuo. The resulting solid was recrystallized from EtOH to give the title compound (15 mg) as an off-white solid.

MS (ESI+): [M+H]+ 414.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.00-1.16 (4H, m), 2.23-2.31 (1H, m), 3.85 (3H, s), 5.23 (2H, s), 6.01-6.10 (2H, m), 7.04 (1H, d, J=8.7 Hz), 7.23 (1H, d, J=3.4 Hz), 7.48-7.54 (2H, m), 7.59 (1H, d, J=7.7 Hz).

4-((4-Bromo-2-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) (4-Bromo-2-thienyl)methanol

The title compound was obtained in step C in example 239 as a mixture with (4,5-difluoro-2-thienyl)methanol and (4-bromo-5-fluoro-2-thienyl)methanol.

1 H NMR (400 MHz, CDCl 3 ): δ 1.82-1.88 (1H, m), 4.80 (2H, d, J=6.0 Hz), 6.93 (1H, s), 7.17 (1H, s).

B) 4-((4-Bromo-2-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of the title compound, 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4,5-difluoro-2-thienyl)methoxy)pyridin-2(1H)-one and 4-((4-bromo-5-fluoro-2-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one obtained in step D in example 219 was subjected to HPLC separation (C18, mobile phase: H 2 O/CH 3 CN (0.1% TFA included)). The solution was neutralized with saturated Na 2 CO 3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , filtered through a plug of silica gel, and concentrated in vacuo. The residual solid was recrystallized from EtOH to give the title compound (30.0 mg) as an off-white solid.

MS (ESI+): [M+H]+ 457.1.

1 H NMR (300 MHz, DMSO-d 6 ): δ 0.98-1.15 (4H, m), 2.22-2.30 (1H, m), 3.85 (3H, s), 5.34 (2H, s), 6.02-6.10 (2H, m), 7.01-7.07 (1H, m), 7.31 (1H, d, J=1.5 Hz), 7.48-7.54 (2H, m), 7.58 (1H, d, J=7.5 Hz), 7.74 (1H, d, J=1.5 Hz).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-(trifluoromethyl)-2-furyl)methoxy)pyridin-2(1H)-one

To a suspension of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (400 mg) and (5-(trifluoromethyl)-2-furyl)methanol (462 mg) in THF (40 ml) were added tributylphosphine (1.06 ml) and 1,1′-(azodicarbonyl)dipiperidine (1.08 g) at 60° C., and the mixture was stirred for 3 h. After the solvent was evaporated, the residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). Then the resulting solid was recrystallized from EtOH-hexane to give the title compound (313 mg) as an off-white solid.

MS (ESI+): [M+H]+ 430.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.00-1.15 (4H, m), 2.22-2.31 (1H, m), 3.86 (3H, s), 5.23 (2H, s), 6.05-6.13 (2H, m), 6.92 (1H, d, J=3.1 Hz), 7.05 (1H, d, J=8.3 Hz), 7.29 (1H, d, J=2.5 Hz), 7.49-7.56 (2H, m), 7.59 (1H, d, J=7.3 Hz).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-(trifluoromethyl)-2-thienyl)methoxy)pyridin-2(1H)-one hydrochloride

HCl (4 M in EtOAc, 0.146 ml) was added to a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-(trifluoromethyl)-2-thienyl)methoxy)pyridin-2(1H)-one (260 mg) in EtOAc (5 ml), and the mixture was stirred at room temperature for 2 h. The resulting precipitate was collected by filtration and washed with EtOAc. The solid was recrystallized from EtOH-IPE to give the title compound (210 mg) as a white solid.

MS (ESI+): [M+H]+ 446.4.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.31-1.46 (4H, m), 2.53-2.61 (1H, m), 4.02 (3H, s), 5.47 (2H, s), 6.11 (1H, s), 6.17 (1H, dd, J=1.4, 7.7 Hz), 7.36-7.44 (1H, m), 7.48 (1H, d, J=8.0 Hz), 7.64 (1H, d, J=7.8 Hz), 7.68-7.73 (1H, m), 7.77 (1H, d, J=8.5 Hz), 8.02 (1H, s).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorophenoxy)methyl)pyridin-2(1H)-one

A) Methyl 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-2-oxo-1,2-dihydropyridine-4-carboxylate

To a mixture of 6-bromo-2-cyclopropyl-1-methyl-1H-benzimidazole (984 mg), methyl 2-oxo-1,2-dihydropyridine-4-carboxylate (600 mg), potassium carbonate (1.08 g) and dioxane (25 ml) were added CuI (298 mg) and trans-N,N′-dimethylcyclohexane-1,2-diamine (223 mg), and the mixture was heated at 80° C. for 12 h. The mixture was concentrated in vacuo, and diluted with DCM. The mixture was washed with brine, dried over Na 2 SO 4 , concentrated in vacuo, and purified by column chromatography (MeOH/DCM) to give the title compound (800 mg) as a white solid.

MS (ESI+): [M+H]+ 324.0.

B) 1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(hydroxymethyl)pyridin-2(1H)-one

To a stirred solution of methyl 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-2-oxo-1,2-dihydropyridine-4-carboxylate (800 mg) in DCM (20 ml) was added diisobutylaluminum hydride (1.0 M in toluene, 1.04 ml) at −78° C., and the mixture was stirred at same temperature for 2 h. The reaction mixture was then quenched with a mixture of MeOH (2 ml) and water (2 ml), filtered through celite and the resulting filtrate was concentrated in vacuo. The residue was purified by column chromatography (MeOH/DCM) to give the title compound (350 mg) as a yellow solid.

MS (ESI+): [M+H]+ 296.0.

C) 1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorophenoxy)methyl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(hydroxymethyl)pyridin-2(1H)-one (150 mg), 4-fluorophenol (114 mg) and tributylphosphine (307 mg) in THF (5 ml) was added 1,1′-(azodicarbonyl)dipiperidine (385 mg), and the mixture was stirred at 60° C. for 4 h. The mixture was concentrated in vacuo, and diluted with DCM. The mixture was washed with water and brine successively, dried over Na 2 SO 4 , concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (40 mg) as a white solid.

MS (ESI+): [M+H]+ 390.2.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.05-1.10 (4H, m), 2.27-2.28 (1H, m), 3.85 (3H, s), 5.06 (2H, s), 6.33 (1H, d, J=7.0 Hz), 6.51 (1H, s), 7.04-7.09 (3H, m), 7.17 (2H, t, J=8.7 Hz), 7.53 (1H, d, J=8.4 Hz), 7.57 (1H, s), 7.67 (1H, d, J=7.0 Hz).

4-((4-Bromo-5-fluoro-2-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) (4-Bromo-5-fluoro-2-thienyl)methanol

The title compound was obtained in step C in example 239 as a mixture with (4,5-difluoro-2-thienyl)methanol and (4-bromo-2-thienyl)methanol.

1 H NMR (400 MHz, CDCl 3 ): δ 4.68 (2H, dd, J=5.8, 2.0 Hz), 6.62 (1H, d, J=3.1 Hz).

B) 4-((4-Bromo-5-fluoro-2-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of the title compound, 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4,5-difluoro-2-thienyl)methoxy)pyridin-2(1H)-one and 4-((4-bromo-2-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one obtained in step D in example 219 was subjected to HPLC separation (C18, mobile phase: H 2 O/CH 3 CN (0.1% TFA included)). The solution was neutralized with saturated Na 2 CO 3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO 4 , filtered through a plug of silica gel, and concentrated in vacuo. The residual solid was recrystallized from EtOH to give the title compound (10.0 mg) as an off-white solid.

MS (ESI+): [M+H]+ 475.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.01-1.14 (4H, m), 2.23-2.31 (1H, m), 3.85 (3H, s), 5.26 (2H, s), 6.00-6.12 (2H, m), 7.04 (1H, d, J=8.5 Hz), 7.18 (1H, d, J=2.8 Hz), 7.52 (2H, d, J=3.6 Hz), 7.60 (1H, s).

4-((4-Chlorophenoxy)methyl)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(hydroxymethyl)pyridin-2(1H)-one (150 mg), 4-chlorophenol (130 mg) and tributylphosphine (514 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (641 mg), and the mixture was stirred at 60° C. for 4 h. The mixture was concentrated in vacuo, and diluted with DCM. The mixture was washed with water and brine successively, dried over Na 2 SO 4 , concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (45 mg) as a white solid.

MS (ESI+): [M+H]+ 406.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.05-1.10 (4H, m), 2.27 (1H, m), 3.85 (3H, s), 5.08 (2H, s), 6.32 (1H, d, J=6.9 Hz), 6.51 (1H, s), 7.06-7.08 (3H, m), 7.38 (2H, d, J=8.8 Hz), 7.53 (1H, d, J=8.5 Hz), 7.57 (1H, s), 7.68 (1H, d, J=7.0 Hz).

1-(2-Ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-fluorothiophen-2-yl)methoxy)pyridin-2(1H)-one

To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (224 mg), (5-fluorothiophen-2-yl)methanol (100 mg) and tributylphosphine (750 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (956 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was concentrated in vacuo, and diluted with DCM. The mixture was washed with water and brine successively, dried over Na 2 SO 4 , concentrated in vacuo and purified by silica gel column chromatography (MeOH/DCM) followed by preparative HPLC to afford the title compound (20 mg) as a white solid.

MS (ESI+): [M+H]+ 384.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.33 (3H, t, J=7.5 Hz), 2.90 (2H, q, J=7.4 Hz), 3.74 (3H, s), 5.23 (2H, d, J=2.4 Hz), 6.04-6.06 (2H, m), 6.68 (1H, dd, J=2.1, 3.9 Hz), 7.01 (1H, t, J=3.7 Hz), 7.06 (1H, dd, J=1.9, 8.4 Hz), 7.53 (1H, d, J=1.8 Hz), 7.57-7.60 (2H, m).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-(trifluoromethyl)phenoxy)methyl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 243 using 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(hydroxymethyl)pyridin-2(1H)-one and 4-trifluoromethylphenol.

MS (ESI+): [M+H]+ 440.2.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-(difluoromethyl)-2-thienyl)methoxy)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (78 mg), (5-(trifluoromethyl)-2-thienyl)methanol (77 mg) and tributylphosphine (168 mg) in THF (3 ml) was added 1,1′-(azodicarbonyl)dipiperidine (210 mg), and the reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (48.5 mg) as a white solid.

MS (ESI+): [M+H]+ 428.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.95-1.16 (4H, m), 2.22-2.31 (1H, m), 3.85 (3H, s), 5.41 (2H, s), 6.02-6.12 (2H, m), 7.05 (1H, d, J=8.3 Hz), 7.31 (1H, t, J=56.0 Hz), 7.29 (1H, brs), 7.43 (1H, brs), 7.48-7.55 (2H, m), 7.59 (1H, d, J=7.7 Hz).

4-(((5-Chloropyridin-2-yl)oxy)methyl)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 243 using 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(hydroxymethyl)pyridin-2(1H)-one and 5-chloropyridin-2-ol.

MS (ESI+): [M+H]+ 407.2.

4-((5-Bromo-3-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (98 mg), (5-bromo-3-thienyl)methanol (135 mg) and tributylphosphine (211 mg) in THF (3 ml) was added 1,1′-(azodicarbonyl)dipiperidine (264 mg), and the reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (48.8 mg) as a white solid.

MS (ESI+): [M+H]+ 456.0.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.97-1.17 (4H, m), 2.15-2.34 (1H, m), 3.85 (3H, s), 5.08 (2H, s), 5.99 (1H, s), 6.07 (1H, d, J=5.5 Hz), 7.04 (1H, d, J=8.8 Hz), 7.30 (1H, s), 7.52 (2H, d, J=3.8 Hz), 7.58 (1H, d, J=7.4 Hz), 7.67 (1H, s).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to step C in example 243 using 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(hydroxymethyl)pyridin-2(1H)-one and 2-fluoro-5-trifluoromethyl-pyridine.

MS (ESI+): [M+H]+ 441.2.

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-(trifluoromethyl)-3-thienyl)methoxy)pyridin-2(1H)-one

A mixture of 4-chloro-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (800 mg), (5-(trifluoromethyl)-3-thienyl)methanol (972 mg), cesium carbonate (2.61 g) and DMF (8 ml) was stirred at 80° C. overnight. The mixture was poured into water and extracted with EtOAc-THF. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH-water to give the title compound (258 mg) as a white solid.

MS (ESI+): [M+H]+ 446.3.

1 H NMR (300 MHz, DMSO-d 6 ): δ 1.00-1.15 (4H, m), 2.18-2.33 (1H, m), 3.85 (3H, s), 5.16 (2H, s), 6.01 (1H, d, J=2.7 Hz), 6.09 (1H, dd, J=2.7, 7.6 Hz), 7.04 (1H, dd, J=2.0, 8.5 Hz), 7.48-7.55 (2H, m), 7.59 (1H, d, J=7.6 Hz), 7.81 (1H, d, J=1.3 Hz), 8.06 (1H, d, J=1.5 Hz).

4-((1RS,2RS)-2-(4-chlorophenyl)cyclopropyl)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) 4-Bromo-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a suspension of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (2 g) in DMF (35 ml) was added phosphoryltribromide (2.45 g) at room temperature, and the mixture was stirred at 50° C. overnight. The mixture was poured into saturated NaHCO 3 solution, and extracted with EtOAc. The organic layer was washed with water and brine successively, dried over MgSO 4 and concentrated in vacua. The resulting residual solid was recrystallized from EtOH-hexane to give the title compound (1.70 g) as a brown solid.

MS (ESI+): [M+H]+ 345.1.

B) ((2RS,3SR)-2-(4-chlorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)(trimethyl)silane

To a solution of 2-((E)-2-(4-chlorophenyl)ethenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg) and Pd(OAc) 2 (127 mg) in Et 2 O (10 ml) was added trimethylsilyldiazomethane (2.83 ml), and the mixture was stirred at room temperature for 3 h. The mixture was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (260 mg) as an oil.

1 H NMR (400 MHz, DMSO-d 6 ): δ −0.36 (9H, s), 0.14 (1H, t, J=9.0 Hz), 0.35-0.43 (1H, m), 1.11 (12H, s), 2.32-2.39 (1H, m), 7.12-7.27 (4H, m).

C) 4-((1RS,2RS)-2-(4-chlorophenyl)-3-(trimethylsilyl)cyclopropyl)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 4-bromo-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (108 mg), ((2RS,3SR)-2-(4-chlorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)(trimethyl)silane (110 mg), potassium carbonate (130 mg), PdCl 2 (dppf) (11.5 mg), THF (6 ml) and water (2.0 ml) was heated at 70° C. overnight. The mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO 4 , concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (26.0 mg) as a white solid.

MS (ESI+): [M+H]+ 488.2.

D) 4-((1RS,2RS)-2-(4-chlorophenyl)cyclopropyl)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 4-((1RS,2RS)-2-(4-chlorophenyl)-3-(trimethylsilyl)cyclopropyl)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (26 mg), TBAF (1.0 M in THF, 0.533 ml) and THF (1 ml) was heated at 100° C. under microwave irradiation for 1 h. The mixture was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (9.2 mg) as a white solid.

MS (ESI+): [M+H]+ 416.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.00-1.14 (4H, m), 1.51-1.61 (2H, m), 2.10-2.18 (1H, m), 2.22-2.30 (1H, m), 2.36-2.44 (1H, m), 3.85 (3H, s), 6.14 (1H, d, J=6.5 Hz), 6.31 (1H, s), 7.06 (1H, d, J=8.5 Hz), 7.24 (2H, d, J=8.2 Hz), 7.35 (2H, d, J=8.0 Hz), 7.48-7.60 (3H, m

1-(1,2-Dimethyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one

A mixture of 6-bromo-1,2-dimethyl-1H-benzimidazole (500 mg), 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (487 mg), CuI (423 mg), N,N′-dimethyl-1,2-ethanediamine (0.236 ml), potassium carbonate (921 mg) and DMSO (10 ml) was stirred at 150° C. for 1 h. 28% NH 3 solution was added to the resulting mixture, and the solid was washed with water. The solid was purified by NH silica gel column chromatography (hexane/EtOAc), followed by recrystallization from EtOAc-hexane to give the title compound (200 mg) as a white solid.

MS (ESI+): [M+H]+ 364.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 2.55 (3H, s), 3.73 (3H, s), 5.14 (2H, s), 5.99 (1H, s), 6.09 (1H, d, J=6.8 Hz), 7.06 (1H, d, J=8.5 Hz), 7.26 (2H, t, J=8.7 Hz), 7.45-7.64 (5H, m).

4-(1-Benzothiophen-5-ylmethoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 4-chloro-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), benzo[b]thiophen-5-ylmethanol (110 mg), cesium carbonate (326 mg) and DMF (3 ml) was heated at 100° C. overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO 4 , concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (15 mg) as a white solid.

MS (ESI+): [M+H]+ 428.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.00-1.15 (4H, m), 2.22-2.31 (1H, m), 3.85 (3H, s), 5.28 (2H, s), 6.02 (1H, s), 6.11 (1H, d, J=7.4 Hz), 7.04 (1H, d, J=8.4 Hz), 7.43-7.54 (4H, m), 7.58 (1H, d, J=7.5 Hz), 7.82 (1H, d, J=5.3 Hz), 8.00 (1H, s), 8.06 (1H, d, J=8.3 Hz).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-(trifluoromethyl)-1,3-thiazol-2-yl)methoxy)pyridin-2( 1 H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (4-(trifluoromethyl)-1,3-thiazol-2-yl)methanol (65.1 mg) and triphenylphosphine (140 mg) in THF (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (125 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (26.5 mg) as a white solid.

MS (ESI+): [M+H]+ 447.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.97-1.16 (4H, m), 2.27 (1H, brs), 3.85 (3H, s), 5.56 (2H, s), 6.08 (1H, brs), 6.17 (1H, d, J=7.2 Hz), 7.05 (1H, d, J=9.3 Hz), 7.47-7.57 (2H, m), 7.64 (1H, d, J=8.0 Hz), 8.61 (1H, s).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(2,3-dihydro-1-benzofuran-5-ylmethoxy)pyridin-2 (1H)-one

A mixture of 4-chloro-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (2,3-dihydrobenzofuran-5-yl)methanol (100 mg), cesium carbonate (326 mg) and DMF (3 ml) was heated at 100° C. overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO 4 , concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (40 mg) as a white solid.

MS (ESI+): [M+H]+ 414.4.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.00-1.13 (4H, m), 2.22-2.32 (1H, m), 3.20 (2H, t, J=8.5 Hz), 3.85 (3H, s), 4.55 (2H, t, J=8.5 Hz), 5.02 (2H, s), 5.98 (1H, brs), 6.05 (1H, d, J=7.3 Hz), 6.78 (1H, d, J=8.3 Hz), 7.04 (1H, d, J=8.9 Hz), 7.19 (1H, d, J=8.2 Hz), 7.33 (1H, s), 7.48-7.61 (3H, m).

4-((5-Chloro-1,2,4-thiadiazol-3-yl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

The title compound was obtained in an analogous manner to example 190 using 5-chloro-3-(chloromethyl)-1,2,4-thiadiazole and 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-ya)-4-hydroxypyridin-2(1H)-one.

MS (ESI+): [M+H]+ 414.3.

4-((5-Bromo-2-furyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) 4-Chloro-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a suspension of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (75 g) in DMF (1.3 L) was added phosphorus oxychloride (29.8 ml) at room temperature, and the mixture was stirred at 45-50° C. under Ar atmosphere for 26 h. The mixture was poured into EtOAc (1.5 L), and washed with saturated NaHCO 3 solution (1.5 L). The organic layer was separated, and aqueous layer was extracted with EtOAc (2.0 L) two times. The combined organic layer was washed with brine (1.0 L), dried over Na 2 SO 4 and concentrated in vacuo. The residue was dissolved in EtOAc/THF (1/1, 700 ml), and NH silica gel (100 g) was added to the solution. The mixture was filtered through a plug of NH silica gel (500 g) with EtOAc as an eluent to give the title compound (47.0 g) as a pale yellow solid.

MS (ESI+): [M+H]+ 300.2.

B) 4-((5-Bromo-2-furyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a solution of 4-chloro-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (150 mg) and (5-bromo-2-furyl)methanol (177 mg) in toluene (2.0 ml) was added potassium tert-butoxide (112 mg) at 100° C., and the mixture was stirred for 30 min. The mixture was quenched with water (2 ml), and the precipitate was collected. The resulting solid was recrystallized from EtOH—H 2 O to give the title compound (158 mg) as an off-white solid.

MS (ESI+): [M+H]+ 441.1.

1 H NMR (400 MHz, DMSO-d 5 ): δ 0.99-1.14 (4H, m), 2.22-2.31 (1H, m), 3.85 (3H, s), 5.11 (2H, s), 6.03-6.10 (2H, m), 6.63 (1H, d, J=3.0 Hz), 6.74 (1H, d, J=2.8 Hz), 7.05 (1H, d, J=8.5 Hz), 7.51 (2H, d, J=4.9 Hz), 7.58 (1H, d, J=7.9 Hz).

4-((5-Bromopyridin-2-yl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (5-bromopyridin-2-yl)methanol (66.8 mg) and triphenylphosphine (140 mg) in THF (6 ml) was added bis(2-methoxyethyl) azodicarboxylate (125 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by silica gel column chromatography (hexane/EtOAc to EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (25.2 mg) as a white solid.

MS (ESI+): [M+H]+ 452.3.

1 H NMR (400 MHz, DMSO-d 5 ): δ 0.98-1.15 (4H, m), 2.26 (1H, brs), 3.85 (3H, s), 5.21 (2H, s), 5.96 (1H, brs), 6.13 (1H, d, J=7.5 Hz), 7.04 (1H, d, J=8.4 Hz), 7.47-7.57 (3H, m), 7.60 (1H, d, J=8.0 Hz), 8.15 (1H, d, J=7.5 Hz), 8.75 (1H, s).

1-(2-Ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((4-(trifluoromethyl)-1,3-thiazol-2-yl)methoxy)pyridin-2(1H)-one

To a solution of 1-(2-ethyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (400 mg), (4-(trifluoromethyl)-1,3-thiazol-2-yl)methanol (544 mg) and triphenylphosphine (1.17 g) in THF (35 ml) was added bis(2-methoxyethyl) azodicarboxylate (1.04 g) at room temperature. After 3 h, the mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/MeOH), followed by recrystallization from IPA-IPE to give the title compound (175 mg) as a white solid.

MS (ESI+): [M+H]+ 435.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.34 (3H, t, J=7.4 Hz), 2.91 (2H, q, J=7.5 Hz), 3.74 (3H, s), 5.57 (2H, s), 6.08 (1H, s), 6.13-6.22 (1H, m), 7.08 (1H, d, J=8.4 Hz), 7.55 (1H, s), 7.58-7.68 (2H, m), 8.61 (1H, s).

4-((5-Bromo-3-furyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

To a solution of 5-bromo-3-furoic acid (215 mg) in THF (2 ml) were added triethylamine (0.314 ml) and isobutyl chloroformate (0.175 ml) at 0° C., and the mixture was stirred at the same temperature for 1 h. To this mixture was added LiBH 4 (54 mg) at 0° C., and the mixture was stirred at room temperature for 1 h. Additional LiBH 4 (10 mg) was added, and the mixture was stirred at room temperature for further 2 h. The reaction mixture was quenched with saturated NaHCO 3 solution at 0° C., and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO 3 solution and brine successively, dried over MgSO 4 and concentrated in vacuo. The resulting residue was dissolved in toluene (2.0 ml). 4-Chloro-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (150 mg) and potassium tert-butoxide (112 mg) were added to the solution, and the mixture was stirred at 100° C. for 30 min. The mixture was quenched with water (2 ml)/IPE (2 ml), and the resulting solid was recrystallized from EtOH—H 2 O to give the title compound (57.0 mg) as a pale yellow solid.

MS (ESI+): [M+H]+ 441.1.

1 H NMR (400 MHz, DMSO-d 6 ): δ 0.98-1.15 (4H, m), 2.21-2.32 (1H, m), 3.85 (3H, s), 4.99 (2H, s), 5.96-6.09 (2H, m), 6.72 (1H, s), 7.04 (1H, d, J=8.2 Hz), 7.47-7.61 (3H, m), 7.95 (1H, s).

1-(2-Cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-(pyridin-2-ylmethoxy)pyridin-2(1H)-one hydrochloride

To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (500 mg) in DMF (5 ml) were added 2-(bromomethyl)pyridine hydrobromide (450 mg) and potassium carbonate (491 mg) at room temperature, and the mixture was stirred for 3 hour. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO 3 solution and brine successively, dried over MgSO 4 , concentrated in vacuo, and purified by NH silica gel column chromatography (EtOAc/hexane). The resulting solid was treated with HCl (4 M in EtOAc, 0.444 ml) to give the title compound (232 mg) as white crystals.

MS (ESI+): [M+H]+ 373.2.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.05 (2H, d, J=3.8 Hz), 1.16 (2H, d, J=8.3 Hz), 2.23-2.32 (1H, m), 2.58 (3H, s), 5.29 (2H, s), 6.07 (1H, d, J=2.3 Hz), 6.30 (1H, dd, J=2.4, 7.7 Hz), 7.41-7.53 (1H, m), 7.62 (1H, d, J=7.9 Hz), 7.72 (1H, d, J=7.8 Hz), 7.85-7.92 (1H, m), 7.93-8.01 (2H, m), 8.65 (1H, d, J=4.5 Hz), 9.00 (1H, s).

4-((5-Chloropyrimidin-2-yl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A) ((1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-2-oxo-1,2-dihydropyridin-4-yl)oxy)acetonitrile

A mixture of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (3.0 g), bromoacetonitrile (0.82 ml), potassium carbonate (4.42 g) and DMF (10 ml) was stirred at 80° C. for 2 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by silica gel column chromatography (hexane/EtOAc). The resulting solid was washed with IPE to give the title compound (2.39 g) as a pale yellow solid.

MS (ESI+): [M+H]+ 321.1.

B) 2-((1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-2-oxo-1,2-dihydropyridin-4-yl)oxy)ethanimidamide hydrochloride

To a solution of ((1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-2-oxo-1,2-dihydropyridin-4-yl)oxy)acetonitrile (300 mg) in MeOH (4 ml) was added sodium methoxide (2.5 mg), and the mixture was stirred at room temperature for 4 h. NH 4 Cl (52.6 mg) was added to the mixture, and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residual solid was washed with IPA-IPE to give the title compound (368 mg) as a light brown solid.

MS (ESI+): [M+H]+ 338.1.

C) 4-((5-Chloropyrimidin-2-yl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one

A mixture of 2-((1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-2-oxo-1,2-dihydropyridin-4-yl)oxy)ethanimidamide hydrochloride (100 mg), 2-chloro-3-(dimethylamino)-N,N-dimethylprop-2-en-1-iminium hexafluorophosphate (0.82 ml), sodium methoxide (43.3 mg) and MeOH (10 ml) was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was partitioned between EtOAc and water. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (56 mg) as a white solid.

MS (ESI+): [M+H]+ 408.3.

1-(2-Ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-(trifluoromethyl)-3-thienyl)methoxy)pyridin-2(1H)-one

To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (300 mg), (5-(trifluoromethyl)-3-thienyl)methanol (352 mg) and triphenylphosphine (877 mg) in THF (10 ml) was added bis(2-methoxyethyl) azodicarboxylate (783 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from IPA-IPE to give the title compound (70.0 mg) as a white solid.

MS (ESI+): [M+H]+ 434.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.33 (3H, t, J=7.6 Hz), 2.91 (2H, d, J=7.4 Hz), 3.74 (3H, s), 5.17 (2H, s), 6.02 (1H, s), 6.10 (1H, d, J=10.0 Hz), 7.07 (1H, d, J=9.2 Hz), 7.53 (1H, s), 7.59 (2H, d, J=8.3 Hz), 7.81 (1H, s), 8.06 (1H, s).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((2-(trifluoromethyl)-1,3-thiazol-4-yl)methoxy)pyridin-2(1H)-one

To a mixture of 4-bromo-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (2-(trifluoromethyl)thiazol-4-yl)methanol (80 mg) and toluene (5 ml) was added potassium tert-butoxide (98 mg) at 100° C., and the mixture was stirred at the same temperature overnight. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (29.0 mg) as a white solid.

MS (ESI+): [M+H]+ 447.3.

1 H NMR (400 MHz, DMSO-d 6 ): δ 1.00-1.14 (4H, m), 2.27 (1H, brs), 3.85 (3H, s), 5.32 (2H, s), 6.05-6.15 (2H, m), 7.05 (1H, d, J=8.7 Hz), 7.52 (2H, d, J=4.9 Hz), 7.60 (1H, d, J=7.7 Hz), 8.33 (1H, s).

1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-(trifluoromethyl)pyrazin-2-yl)methoxy)pyridin-2(1H)-one

A) 2-(Bromomethyl)-5-(trifluoromethyl)pyrazine

To a solution of 2-methyl-5-(trifluoromethyl)pyrazine (1 g) in trifluoromethylbenzene (10 ml) was added N-bromosuccinimide (1.21 g) at room temperature, and the mixture was heated at 90° C. for 30 min. To the mixture was then added azobisisobutyronitrile (0.051 g), and the mixture was stirred for 7 h. The mixture was cooled, and the solvent was evaporated. The residue was purified by column chromatography (hexane/EtOAc) to give the title compound (404 mg) as a pale yellow oil.

1 H NMR (400 MHz, DMSO-d 6 ): δ 4.88 (2H, s), 9.03 (1H, s), 9.20 (1H, s).

B) 1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-(trifluoromethyl)pyrazin-2-yl)methoxy)pyridin-2(1H)-one

The title